Asari are an all female species that reproduces by randomizing part of their DNA using that of any other species regardless of gender as a template. Indeed they're encouraged to do this, and two Asari having a daughter together gets rather looked down upon in their society. Somewhat understandable, in that pureblood couples supposedly increase the chance of Ardat-Yakshi being produced. Liara T'Soni was an Asari romance option for both male and female Shepards from the very first game.
Joker and EDI in the third game. Him being a human and her, an AI controlling a robot body.
Mordin mentions in passing that he's gotten a surprising number of passes from other species... but then he's Mordin so that may not count. He also mentions that Salarians like himself are considered as quite attractive by certain unlikely species.
He talks a lot about interspecies sex. He even gives youThe Talk of the... biological implications of such romance. He notes that chafing will result and recommends you not to *cough* ...ingest.
One time you visit him, he tells you he's currently busy with dealing with an outbreak of a sexually transmitted disease, that is only present in varren. "Implications unpleasant."
After completing a certain quest line on the krogan homeworld EDI will inform you that "We have received several breeding requests for Grunt... and one for Shepard".
A widely popular in-universe film called Fleet and Flotilla is about a turian and quarian pairing. This gets mentioned in Mass Effect 2 by one unlucky-in-love turian. There is also a videogame. The kicker? Legion has played it. And he's terrible at it.
The Citadel DLC for 3 reveals that Tali apparently is a big fan of the musical version of Fleet and Flotilla. It also reveals she borrowed some lines from the movie to give her the courage to admit her feelings for Shepard, in her romance arc in Mass Effect 2.
If Shepard doesn't romance either Garrus or Tali and both survive to Mass Effect 3, they end up together. Both are apparently fans of Fleet and Flotilla, humorously enough.
Turian-quarian romances are a bit of a thing, apparently, as they're biologically compatible, at least in terms of chirality. So there's less of a chance of one or both partners suffering a violent biochemical reaction in case of...ingestion.
Curiously, interspecies couples became significantly more prevalent in background scenes as the series continues, especially in Mass Effect 3, which has seemingly more of them than same-species ones. Such is life during an Alien Invasion — as Joker points out, people have a lot more to worry about than a little public disapproval.
In the Citadel DLC, if you get a female Shepard drunk enough, and she's on good enough terms with him, she and Javik can have a one-nighter. Which they will never speak of again.
In Mass Effect: AndromedaPathfinder Ryder can romance several alien characters, including Peebee (asari), Vetra (turian) and Jaal (angara, a new species native to Andromeda), who are available to male and female Ryder. Both Ryders can also have a fling with asari reporter Keri T'Vessa, and male Ryder can also woo the angara Avela Kjar.
Several NPCs and background characters are shown or implied to be in an Interspecies Romance as well, such Sloane Kelly with her turian second-in-command Kaetus.
Peebee herself is the product of an asari-elcor couple.
BioWare preceded this with the Gay Option in Knights of the Old Republic. Juhani is of a felinoid alien species called the Cathar. It's also heavily implied that she and a female human Padawan were a bit more than just friends.
The Brotherhood of Shadow mod has Arkanian offshoot Koybayasi and Twi'lek Channa Mae/Shadow/Sera Degana. It's a surprisingly sweet note in a very frightening mod.
Each game starting with Morrowind features an in-game semi-pornographic play titled The Lusty Argonian Maid. In it, the main character, an Imperial (human) named "Crantus Colto", is looking to get his "spear polished" by the titular Argonian (Lizard Folk) maid. Skyrim introduces a sequel.
Another in-game book introduced in Daggerfall, The Real Barenziah, tells the story of the future queen of Morrowind and Wayrest, Barenziah. In it, she (a Dunmer, aka "Dark Elf") has sex with a Khajiit (Cat Folk) named Therris so that he will induct her into the Thieves' Guild. (As is the case with real life felines, Khajiit males have sharp spines on their penises, as Barenziah finds out the hard way.) Later, Barenziah has an affair with the human Emperor Tiber Septim, and becomes pregnant by him. (As a bastard child with a Dunmer mistress would be very inconvenient for the Emperor, he orders Barenziah to have a magical abortion.) The books are also in Morrowind and Oblivion, although the version present in both is censored. The book The Last Scabbard of Akrash provides another Dunmer/Khajiit example, though it is less detailed about the actual act.
The in-game book Interspecies Phylogeny discusses this trope from a scholarly perspective. It is stated that each race of Men (Imperial, Breton, Redguard, Nord) and Mer ("Elves" - Altmer, Dunmer, Bosmer) can indeed interbreed, with the race of the offspring being virtually identical to the mother (averting All Genes Are Codominant) with a few of the father's traits potentially sprinkled in. For example, if an Altmer father and Nord mother produce a child, it wouldn't be a Magic Knight combination of each race. Instead, the child would be almost entirely Nord with the potential of having slight points to his ears or a slightly different skin tone. Over many generations, however, this can result in offspring closer to Half-Human Hybrids. This is in fact how the Bretons got their start as a race, with their (human) ancestors being Breeding Slaves to the Direnni Altmer of High Rock. Further, it notes that although there are tales of human or elf having children with the other races, there are no confirmed reports (Oblivion confirms via first-hand evidence that at least Orcs, who are the Orsimer, or "Changed Elves", can have children with humans (and presumably other elves). As can Cyrodiil-style vampires).
In the backstory, the Tsaesci, a race supposedly made up of "snake vampires" hailing from Akavir who once invaded Tamriel, supposedly left behind offspring with the Tamriellic races who are considered "beautiful, if frightening." (Other sources indicate that the Tsaesci are men little different from those in Tamriel, downplaying the trope if true.)
Also from the backstory, St. Alessia, the Slave Queen who overthrew the Ayleids ("Wild Elves") to found the first Cyrodiilic Empire of Men, was romantically involved with Morihaus, an et'Ada who took on the form of a great humanoid, winged bull. They eventually gave birth to what would become the Minotaur race.
In the religion of the Nine Divines, Mara, the Love Goddess of the Nine Divines (with a focus on on commitment, family, fertility, and matrimony compared to Dibella's (another Divine) focus on the carnal and sexual aspects of love) does not place any restrictions on marriage within the religion of the Nine Divines, thus all may marry, irrespective of gender and race, and unite their souls in the holy union.
A Romance Sidequest available for any male character in Morrowind is a Khajiit woman. She's not picky, of course.
One side quest quest involves finding a Dunmer thief who stole a Breton noblewoman's jewellery. It turns out that she's not actually too concerned about the jewellery, but the thief himself. Finding this man reveals that her love is, in fact, requited.
A quest that is part of both the Thieves Guild and Fighters Guild quest lines tasks you with gaining the support of Hrundi, a Nord man who was the Number Two to the Reasonable Authority Figure former Guild Master before the current (very corrupt) Guild Master took over. You can learn that he has taken on a Dunmer lover, and can Blackmail him with that fact for his support. (The "interspecies" part itself isn't the reason for the blackmail, rather, it's because this information puts his lover in danger if the corrupt Guild Master finds out about her.)
In Skyrim, you can marry any marriageable character, regardless of race or sex, allowing you to be in one of these. The only races without a marriageable character are the Bosmer (Wood Elves) and Khajiit.
Femme Fatale Rouge (a bat) is officially claimed to have a crush on Knuckles (an echidna) with additionally flirtatious advances on most of the male cast, Dr. Eggman included.
It's sort of hinted in Sonic Rush that Sonic and Blaze the Cat may have a thing for each other.
In the SatAM continuity, Sonic's girlfriend is half chipmunk, half squirrel. In the comics he seems to have built an Unwanted Harem including other animal characters. In both the cartoon and the Archie Comics, he also competed with Antoine (coyote) for Sally's affections — in the comics, this stopped after Antoine became an Official Couple with Bunnie Rabbot (Cyborg rabbit), who first showed a brief hint of having a thing for the cowardly pseudo-French coyote in one episode of the cartoon. And in both canons, Bunnie's attitude towards Sonic, particularly before hooking up with Antoine, could be taken as flirtatious, what with her frequent reference to him as "sugah hog".
Tails (fox, albeit a slightly mutated one) and Cosmo (Seedrian - a species evolved from plants) in Sonic X.
During Sonic Underground, Knuckles gets a new love interest in Sonic's own sister, Sonia. Sonia also had her fair share of romances with Bartley and Stripes. Also, Dingo has a Villainous Crush on her.
Sonic originally had Token Human girlfriend named Madonna early into the development of the original game. She was ultimately dropped when they decided to make the series cuter (such as when they changed the enemies from slightly creepy monsters to the more friendly-looking Badniks).
Agarest Senki has five different human/non-human matchups across the four generations, and the fifth generation can choose one of the girls not chosen in a past generation. As said romances consist of a Syrium (an elf-like race), a neocollom (kitsune) with god's blood on her mother's side of the family, two elven hybrid sisters (half High Elf, half Dark Elf), and a Featherfolk (angel-like Winged Humanoid), this isn't as improbable as it may sound. There's also teasings of a homosexual version; the hermaphroditic god Deeth flirts with Dyshana in female form and gets hit on by Thoma after she mentions she should have shown up in male form. Both Dyshana and Thoma are human.
Pretty much any Dungeons & Dragons-based game (see below) that has any sort of romantic capability will have Interspecies Romance. It's almost blasé in D&D, though some settings make a point of having a xenophobic nation or two - almost always evil or at least repressive to take the moral of the concept from plain obvious to Anvilicious.
For a more old-school reference, there is a sex scene between the Captain and Talana in Star Control 2. It is almost a But Thou Must! although if you refuse enough you can skip it.
There is also Admiral ZEX, who there is not a (canon, at least) sex scene with, despite the fact that he has a very clear interest in the Captain. This is partly because of the fact that he's male and partly because, unlike Talana, he looks nothing like a human.
Sly Cooper has titular character Sly, a raccoon, and Carmelita, a fox. There's also Bentley, a turtle, and Penelope, a mouse. Though with the last one, that fell through in the fourth game.
Breath of Fire I features the neighboring villages of Tantar and Tuntar, one of which is populated entirely by humans and the other is populated entirely by the "forest clan," people who look like this◊. The two villages get along incredibly well, and in fact, when the player first arrives, both are celebrating the fact that the first forest clan/human marriage is about to take place. And it does, though you have to do a bit of a Fetch Quest to save both villages from an imminent threat before the actual wedding. (Forest clan male/human female, if anyone was curious.)
A cutscene in Breath of Fire II retroactively reveals that Ryu (dragon clan) and Nina (bird clan) from Breath of Fire I got together, and the current bird clan as of Breath of Fire II is weaker due to being less pure-blooded due to being descended from that pairing. That's why the bird clan in Breath of Fire II can't shapeshift without a special irreversible ritual, whereas they could go back and forth at will in Breath of Fire I. Much less extreme than the first example, since the clans in question are both basically human with some magical traits added.
The Bird Clan seems to love the species so much, that, by the time of Breath of Fire III, the entire clan have essentially lost their wings, becoming boring old humans. Making the hero and heroine of every Breath of Fire game Ryu of the Dragon Clan and Nina of the Bird Clan doesn't help matters either.
Also in Breath of Fire II, both that generation's Nina (a winged human), and Katt (a half-furry catgirl) develop crushes for Ryu. Ryu's friend Bow (an anthropomorphic bulldog) has a thing for Nina's sister Mina (also a winged human). Sten (a monkey man) tries to blackmail Nina (and later Katt) into a date. And hell, even Ryu's own parents are an interspecies couple (a human and a dragon).
Rand's mother Daisy in Breath of Fire II is of...somewhat debatable race, looking more or less like a human, though slightly larger. Whatever she is, though, she looks absolutely nothing like her very obviously armadillo son, which raises certain questions about his unseen father. Although, to be fair, the female representatives of some races (including Rand's race) tend to look much more human than the males.
Breath of Fire III teases Slap-Slap-Kiss-style Unresolved Sexual Tension between Momo (technically a dog, though the degree of anthropomorphism is so far toward human and the ears look so much more rabbit-like than dog-like that she more like a bunny-girl than anything else) and Rei (weretiger) from time to time.
Bleu/Deis, a somewhat perverted lamia-like snakewoman, who hits on the different Ryus throughout the entire series.
Darkstalkers loves to Ship Tease between Felicia (a catwoman) and Jon Talbain (a werewolf). There's also one between Morrigan (a succubus) and Demitri (a vampire).
There's a Ship Tease between Spyro and Elora (a faun) in the Original Series. Post-Insomniac prefer to pair him with dragons (such as Ember or Cinder), however that doesn't stop girls of other species from flirting with him.
Final Fantasy IV, Cecil and Golbez were sired by Kluya, a Lunarian (that is, an alien from a very, very distant world, who eventually settled on a moon orbiting the game's planet,) from a human mother. Cecil goes on to have children of his own, again with a human mother.
Final Fantasy VII, Aerith, the last Cetra, is the daughter of a human scientist named Gast, and a Cetra woman named Ifalna. Of course, the Ancients are almost entirely human themselves, so there's really not much of an issue here, until Hojo comes along and tries to mate Aerith with Red XIII, a huge talking wolf/lion that is another Last of His Kind. There's no indication that Hojo's idea would have actually worked, though. According to the Compilation, there was at least one more, female, member of Red XIII's race, who had been his mate before he was captured by Shinra.
In Final Fantasy IX, Garnet and Eiko were Summoners, apparently a different species from normal people, since they were born with horns. Also, Zidane's not entirely human either — obvious from the start since he has a tail, but this turns out to be more than a cosmetic quirk. And then there was the Vivi/Quina marriage, which involved a techno-magical construct and an ambiguously gendered giant frog thing.
In Final Fantasy Legend, not only does this occur, but it's so common that nobody bats an eyelash about King Armor (human, or close to it) falling in love with a girl that uses the same sprite as beholders and slimes!
Final Fantasy XI, being an MMO with five humanoid races and all, is bound to have plenty of romance, found both in the player base and story lore. The tragic romance between Raogrimm, a Galka, and Cornelia, a Hume, became the catalyst of war. The main character of Wings of the Goddess, Lilisette, is apparently the offspring of an Elvaan and a Hume, in a game where cross-breeds were never mentioned before. Also, one cannot deny the massive amounts of Tarutaru x Mithra doujin...
Final Fantasy XII has a little shipteasing between Fran and Balthier, particularly in the Pharos after defeating Dr Cid. Revenant Wings expands on this - when Tomaj attempts to romance Fran, she tells him Balthier's methods were different.
Also, there is a sidequest in Rabanastre in which you can pair a Viera up with a Hume. The Hume tells the party that he wouldn't have imagined a Viera/Hume pairing could work until he saw Balthier and Fran.
Final Fantasy XIV, like Final Fantasy XI, has five playable races and there are some NPCs that show interest in another person, regardless of their race. According to Word of God, there are actual pairings of different races, but they are usually hidden from public view due to different pairings generally being frowned upon in most societies. There's also Shiva, an Elezen (humanoid elf) woman from Ishgard's ancient history, who had fallen deeply in love with a dragon, who reciprocated. It's rumored she laid with him, but whether this is true or just propaganda because she had taken the side of the dragons during the nation's first conflict with the dragon race is never clarified. It is later explained that dragons pick soulmates purely based on their spiritual bond and love with their mate rather than based on sexual feelings. This may imply that Shiva and her dragon mate simply loved each other for what they were to each other.
Notably, an endgame quest to unlock a dungeon is explained by a gay male couple consisting of a Miq'ote and a Hyur. The dialogue implies the two were forced out of their home village due to discrimination, not due to both being male (though it's possible this is true), but due to their differing races.
Dissidia: Final Fantasy: The Warrior of Light and the goddess of harmony Cosmos seem to have a strong bond with each other. This bond is most prevalent in 012 as he nearly dies in order to protect her from a swarm of Manikins. One just might call it romantic. However, if they do have romantic feelings for one another, it is unknown whether or not either one and/or both of them are oblivious to it. Then subverted when its discovered both are in fact the same species after all.
Hinted at in RuneScape between the main character and Zanik the Cave Goblin. But whether this shipping is wrong or sweet is up in the air for debate. Confirmed by Word of God in Letters From The Hedge with a letter from Zanik saying she's not sure if her romantic interest in you (regardless of gender) is genuine chemistry or residual Mind Screw from being possessed by Bandos, and she needs some time to sort out her feelings.
It is rumored in-universe, but never specifically confirmed or debunked, that Char (a near-human with innate fire powers) was intimate with Zaros (Seren's equally-complicated brother). You can directly ask either of them about this, and they're both vague on the subject.
Blazing Blade, Ninian the half-ice dragon is a possible mate for the human hero Eliwood. There's also Nergal (human) and Aenir (ice dragon), the couple that spawned Ninian and her brother Nils.
Interspecies Romance between Beorcs (Humans by Any Other Name) and Laguz (humans who can shapeshift into animals) is all over the place in Path of Radiance and Radiant Dawn. In fact, some of these romances are either directly or indirectly responsible for most, if not all of the events in the two games. Though in this case it's somewhat justified as Beorc and Laguz share a common ancestry.
In Fire Emblem Awakening, Nowi and Panne are potential wives for the majority of the male characters, and are of the Manakete and Taguel races, respectively. The aforementioned Tiki (now thousands of years old and looking like a young adult) makes a reappearance, but will only be able to marry the Player Character.
In the second half of the game, should Nowi and Panne be married, the players will meet Nowi's half-Manakete daughter Nah and Panne's half-Taguel son Yarne (specifically said in one of Panne's endings to have inherited almost all his genes from his mom). They can marry either their human companions from the second generation, or the Player Character. Any second generation marriage that involves Player Character's own exclusive child, Morgan, will also count if s/he is the produce of the player's own marriage with Panne, Nowi, Nah, Yarne, or Tiki.
In Fire Emblem Fates, Kaden the Kitsune and Keaton the Wolfskin are potential husbands for most of the female characters, including a Female Player Character. Like in Awakening, if Kaden and Keaton are married, the players will be able to recruit their respective hybrid children, Selkie and Velouria, who themselves can marry most of the second generation males or a male Player Character.
The Player Character him/herself, who can transform into a dragon, is revealed to be the produce of a relationship between the human Mikoto and the dragon Anankos. Additionally, any romantic relationship involving his/her own exclusive child, Kana, will always count as this trope (for obvious reasons), though Kana's own degree of human ancestry can vary from 3/4 all the way down to 1/4 depending on who his/her other parent is. In the localization, the Kanas have more limited romantic options - Female Kana can only date the human Kiragi (and maybe Siegbert, when she grows up), while Male Kana will only hook up with the aforementioned Selkie (and maybe either Nina, Rhajat or Mitama, again whe grows up).
Also possible between humans and Sepps (see Endorph ending). Might happen between Revya and Danette in the future after the Danette (male) ending. See Victorious Childhood Friend.
Sepp/human pairings may actually be quite common. One NPC in the game claims to be half human half sepp, Levin (sepp) has a crush on Tricia and may also hook up with Revya (if female) in the Levin-ending. Female Revya can also hook up with Gig, the God of Death in one ending.
The series early as Warcraft 1: Orcs and Humans there was Garona the Half-orc and Griselda and Turok, a female orc and male ogre respectively; Warcraft 3 reveals this coupling produced Mok'nathal (ogre-orc). Less extreme examples have been the inevitable human male/Female elf pairing as with Alleria Windrunner and Turalyon (human), as well as Veressa Windrunner and Rhonin (same combo). There's at least two orc/draenei couples, and one character, Med'an, who's the child of one of those last and Medvih, thus making him 1/4orc 1/4draenei 1/2 human, though you wouldn't know it if you saw him. It's also hinted that Kael'Thas (yet another high elf) had a crush on Jaina Proudmoore (human), and furthermore, many people speculate that Jaina has a romantic relationship with Thrall (orc) (confirmed false in Thrall: Twilight of the Aspects.)
Garona is an aversion of the romance aspect - she was produced via dark sorcery using a dead Draenei and Orc parent.
Marvin and Tamara Wobblesprocket are a married couple. The former is a tiny gnome, and the latter is a human.
Archaeologist Adamant Ironheart (Dwarf) and Priestess Kyleen Il'dinare (Night Elf) seem to have something going on, too. At least, she doesn't mind him calling her "darling".
The Troll Zebu'tan is forever trying to woo the Blood Elf Alys Vol'tyr. She isn't very receptive to his advances, but her dialogue makes it pretty clear that it has little to do with his species; she doesn't want him because she's spoken for and he's a creep.
World of Warcraft has several "Steamy Romance Novels" that can be pickpocketed or looted from NPC humanoids. Most of them involve "Marcus", a male human paladin who has either slept with or dated members of nearly every playable race in the game, from the feasible (night elf and blood elf), odd (a female gnome warlock) to the disturbing (tauren and undead). There's also Anveena (human embodiment of the Sunwell) and Kalecgos (a blue dragon). Possibly also Tyrygosa and Jorad Mace. And now, Jaina and Kalecgos; helps that he has a humanoid form...
Ever play the classic arcade game Joust? When you destroy one of the vulture riders, the vulture lays an egg that you must collect to complete the round. If it is allowed to hatch, an enemy human emerges, and a new flying steed comes in to pick him up. The question is, why does this happen? An explanation comes to mind...
Tales of Rebirth has a gajuma(beastmen) princess loves a huma(human) general seems one-sided until she dies at the end and he realizes that he loves her too, giving it a Bittersweet Ending.
Tales of Symphonia gives us several pairings between humans and elves. Pairings between angels and humans do not count because angels were just humans and half-elves with their bodies modified to resemble that of what people believed angels to look like.
Tales of Symphonia: Dawn of the New World gives us not one but two canon inter-species pairings: Marta/Emil and Aqua/Richter, though the former eventually can live out their lives as humans and the latter is one sided.
In The Sims you can sleep with robots, zombies, vampires, plant-creatures, aliens, werewolves, etc.
Mega Man Zero 4 introduced two characters, Neige (human) and Craft (Reploid). The latter even explicitly stated that he fell in love with her, and their romance is a very important turning point in the game!
Earthworm Jim, whose name speaks for itself, has a huge crush on Princess What's-Her-Name, who is a humanoid insect. On the other hand, if they're really all cows then this trope is averted.
Ar tonelico: Melody of Elemia: a part-RPG, part-dating sim whose dating sim aspects revolve entirely around relationships between humans and Reyvateils - an all-female race of magical girls whose ancestors were artificial intelligences created from scratch using alchemy. You can also date said at least one of said ancestors, who's immortal and still around.
The Legend of Zelda: The Wind Waker, a girl named Maggie asks you to deliver a love-letter to her love at the Forsaken Fortress. As it turns out, the person she met and fell in love with while being held captive there is actually a Moblin — one who is torn between wanting to return the affection and wanting to eat her. In addition, Link gets hit on by the Queen of Fairies. He appears to actually quite like it.
The The Legend of Zelda Oracle games have a good dose of this, too. In Seasons, Link (Hylian) dates the Subrosian pop star Rosa (and, in the manga, draws the romantic attention of his pet chicken, Piyoko). In Ages, Link gets propositioned by the Maku Tree, and Queen Ambi pines for...the undead Piratian Captain. Then again, since he's been stuck in another world for years, he may have been human a long time ago.
The pretty blatant hinting at something between Link and Midna in The Legend of Zelda: Twilight Princess, made tragic by the ending. Link's childhood friend Ilia is also a heavily Implied Love Interest and is a human, though it's difficult to tell if Hylians are really a separate species from humans or not (especially in Twilight Princess, where hylians are referred to as "human").
In The Legend of Zelda: Breath of the Wild, there is Mipha, a Zora, who has strong feelings for Link, a Hylian. She even made him a special set of armor, which is apparently a custom among the Zora for a princess to give to the man she intends to be her husband. There's also another female Zora, Finley, who wants a boyfriend and you can assist her in finding one. She ends up with a Hylian man and despite Finley's body not reaching adulthood yet (she's mentally an adult), the two seem get along well. Finley's mother was also in love with Link when she was younger.
Gerudo are a One-Gender Race of women who find Hylian boyfriends in order to breed. According to Breath of the Wild, the Gerudo really do get boyfriends (most fans previously thought the line referred to them having flings with Hylians). Several Gerudo NPCs mention looking for husbands, and there are even classes in Gerudo Town dedicated on how "voe" work and how to court them.
Crow, the heroine's bird companion from The Longest Journey, claims he's made advances to female birds of multiple species, although it's not clear if his efforts were successful or if he's just making it up.
The series is mentioned in the anime section, but gets another mention due to the prevalence of Hot Skitty-on-Wailord Action, which appears more readily in the games than the anime. However, it is said that all Pokemon are descended from Mew, which would make them technically all one species.
According to Sinnoh legend in the English version of Diamond/Pearl/Platinum, at one point, humans and Pokémon "ate together at one table". This is a Bowdlerization of the original Japanese line that explicitly states marriage occurred between the two. One of the egg groups is called "Humanshape"...
There's one in the storyline of Omega Ruby and Alpha Sapphire that's odd even for two Pokémon; Chaz's Machoke and Lisia's Altaria seem to be a little affectionate towards each other, despite the fact that they aren't even compatible.
Pulseman tells of the titular character being the offspring of a man and an AI. Yes, man and machine had a baby. By combining his DNA and her program core, when he digitised himself inside her.
Most of Ratchet's Girls of the Week in the Ratchet & Clank series qualify. For a slightly more brain-damaging version, there's an amnesiac Captain Qwark apparently once hooking up with a monkey. (This revelation is, naturally, treated as Too Much Information).
In Ōkami, the Ship Tease between Ammy and Issun kicks to high gear minutes prior to entering the Final Dungeon, with some very suggestive lines from Issun. Keep in mind, Issun is a wood sprite roughly the size of a person's hand and Ammy is the sun goddess in wolf form.
There's also the matter of how her son Chibiterasu from Ōkamiden came to be, despite that it's implied the only ones left alive on the celestial plains are the celestials (Something close to humanoid angels) and Wakka.
In Mana Khemia one of the human (sort of) protagonist's possible love interests is a catfolk named Nikki, and if you manage to get her ending, not only do they get married, but they also have kids.
In the Lunar series, it just happens to work out that all the beastfolk characters with romance arcs have human love interests.
Pretty much all of the girls in Thousand Year Door seem to like Mario. All four of his female party members (a Goomba, a talking cloud, a shadow siren, and a mouse) give him a kiss on his cheek at one point. Vivian even comes close to telling him her true feelings for him at the end, but then decides that he'd be much better with Peach.
TEC (a computer) is crushing on Peach (human).
Bowser, a Koopa, also has a crush on Peach. In Super Mario Sunshine, Bowser's son Bowser Jr. thinks that Peach is his mother. However, this is jossed in the ending of the game.
In Dragon Age: Origins, none of the party members with whom you can pursue a romance (consisting of three humans and a male elf) care what race the player character is, be he or she a human, elf, or dwarf. However, if a dwarf, the romantic interlude is as awkward as one might expect.
Dragon Age II has an always-human player character and two elf love interests, neither of whom particularly mind despite the setting's use of Enslaved Elves. Of course, as a hunted former slave himself, Fenris has bigger things to worry about than social taboos, while Merrill seems to decide that the Dalish disapprove of her choices anyway, so what's one more broken rule?
Isabela admits to having slept with humans, elves, and a "dwarf in drag once", but doesn't recommend the last one. She has a history with Zevran established in the first game and becomes Friends with Benefits with Fenris if neither of them are romanced.
While no romance occurs, Merrill once admits to finding the Qunari particularly "easy onthe eyes". If Carver is alive, he has a crush on her, of which she may or may not be aware.
Dragon Age: Inquisition brings back the ability to choose the player character's race, resulting in all the same race combinations as the first game, with Tal-Vashoth / Qunari added to the mix. Solas (an elf) is the only love interest to exclusively date within his own species. As in Origins, if playing as a dwarf, this is the only option available for a romance (unless you count flirting with Scout Harding).
If neither is romanced by the Inquisitor, it's possible for Dorian (human mage) and the Iron Bull (Qunari) to end up together. Also, if the Inquisitor does not romance Sera (elf), she ends up with the Inquisition's arcanist Dagna (dwarf).
Inquisition also potentially allows the Inquisitor to reunite estranged lovers Briala (elf) and Empress Celene (human).
The tie-in novels reveal that King Maric (human) had love affairs with two different elf women, Katriel and Fiona. The latter relationship resulted in the birth of Alistair, one of the potential love interests in Origins.
BioWare did it again in Neverwinter Nights: Hordes of the Underdark, where your character can romance all but one of your companions in Acts II and III (a female drow, a male tiefling, and a female elf ghost), as well as an NPCtrumpet archon.
Guaranteed for female player characters in Neverwinter Nights 2: Mask of the Betrayer, where the romance option is Gann, a hagspawn. Gannayev is the product of an interspecies romance (night hag/human) as a romance option for female PCs. He has no objections based on species either. Neither does Safiya, a human, if the male character is a non-human.
In Brütal Legend, this is how Eddie came to be. Demon Emperor Succoria and her human slave-turned-assassin-turned-lover settled down in the future after Succoria realized that demons would lose control of the world and humans would come to rule the Brutal Land, and she had a Villainous BSOD.
In the art book for Phantasy Star IV, there's a bit of information about what happened to the heroes after the events of the game; Chaz apparently dies of illness sometime before he's thirty, leaving Rika, who has since become a guild hunter, to care for their young son, Rui, by herself.
In Harvest Moon: Animal Parade, either gender of player character can choose a god or mage as their Love Interest. In the latter case, the Witch and Wizard don't seem particularly nonhuman, but there is at least one moment where the Witch makes a point of referring to the main character as a human.
A better example is the Harvest Goddess and Harvest Lord in Animal Parade. A Harvest Goddess is available for marriage in Mineral Town, DS, and Hero of Leaf Valley. Before Animal Parade, what did female players get? A Kappa.
Story of Seasons: Trio of Towns adds a Kitsune named Inari. Inari's gender is the opposite of the player's, so they can marry either gender. Originally Inari was the only bachelor/bachelorette who you couldn't have children with, though an update added the option in.
Rune Factory 3, the main character's parents (although you never actually see them) were a human and a wooly (sheep-like monster). Two of your possible love interests are Kuruna (an univir, a magical horned humanoid) and Pia (a mermaid). Another girl, Raven, is half-human, half-phoenix. Plus there's Gaia's (who is a dwarf) crush on Evelyn (a human).
There's also Rune Factory Frontier, where two of your love interests are Tabatha, an elf, and Iris, a vampire (it would seem vampires in this universe are a separate species, rather than being undead).
A strange example is found in Magna Carta 2, where Celestine falls in love with Argo at first sight. Everyone but Celestine finds it all... Awkward since Argo's a massive creature who looks like a mix between a Dragon and a Hawk. He does eventually warm up to her however.
The implied pairing in Klonoa is between Klonoa (cat-rabbit looking creature) and his friend Lolo (a humanoid girl with a cat tail.)
In one of Telltale's Sam & Max games, Momma Bosco (human) develops a serious but one-sided crush on Max (hyperkinetic rabbity thing). There's later some light Ship Tease with her and Sam (anthropomorphic dog) instead.
Not to mention Sybil marrying the giant robotic Lincoln Memorial.
Girl Stinky and Sal. Stinky's species is a little up in the air due to Retcons (either she's a mermaid or an evil cake in human form), but either way, it's different from Sal, who is a giant talking cockroach.
Strange Journey makes fun of this: whenever Anthony falls in love with a demon, he asks you to go, find the demon and send a message of his love...and every time he tells you he's in love with a demon, the music comes to a dead stop. And every single time, he's put down by the other party in the most humiliating fashion possible, though much of that is his own damn fault (spoiler warning, Anthony: if a demon looks like a little girl, it probably thinks like one, too). Except for Skogsra, who's genuinely thankful she got an apology for his cowardice, and Gemori, who gives him some romantic advice per her job as a god of love.
In Persona 3 and its expansion FES, there is definitely something going on between the MC and Aigis, a robot girl. In Persona 3 Portable it is possible to have a romantic relationship with Ryoji, who is a Shadow with a human mind.
In Persona 4, any romantic relationship Teddie starts would invariably be an Interspecies Romance due to the absence of other living self-aware Shadows in canon at this point of time. It's not limited to Teddie X Human possibilities either; he has been seen trying to start relationships with two robots, one goddess and even one ghost.
Your goal in E.V.O.: Search for Eden is to guide evolution so that you can eventually shack up with Gaia, the personification of the Earth itself. This is also the goal of Bolbox, the main antagonist of the final era. Bolbox happens to be a heavily mutated algae cell who thinks he's a human.
The closest thing to a healthy romance in the first Drakengard game is the bond that develops between Caim (Ax-Crazy human) and Angelus (dragon). In the sequel they get to be Together in Death.
Utawarerumono has a yamagira (humnish creature with dog ears and tail) girl who loves a human(god.)
Dragon Nest has one between a human and an elf. Sadly, the human dies, and there's a string of sidequests about it.
At the ending of the first Shining Force game, it is implied that Mae has a thing for the human player character. Mae is a centaur. It's also implied that Shell the mermaid has a crush on the main character.
There is a side quest called "Mankind and Beastkind" in which you show a Satyros woman named Liese that the love she shares with a human gatekeeper shouldn't be hindered by the fact that they come from two different species.
Your Satyros party member, Aht, has a major crush on the (human) main character, Stocke. He doesn't exactly reciprocate the same feelings, however; not because she's of a different species, but because she's 9.
In Kamidori Alchemy Meister one of the three main love interests is an elf. The main character is also known for getting along with all kinds of supernatural creatures, including elementals, angels, kitsune, succubus and more.
In I Miss the Sunrise, your options of crewmates to pursue romantically are not limited to species. You are free to play a human character who professes their love to Lizard Folk, or vice versa.
BlazBlue gives us Konoe 'Nine' Mercury and Jubei, members of the Six Heroes who defeated the Black Beast prior to the series' events. The former is a human who has passed down her peerless knowledge of magic to the rest of the world, while the latter is a feline beastkin and said to be 'the Strongest Creature Alive'. Eventually, they conceived their child Kokonoe, who inherits traits from both of them, namely Nine's temperament and Jubei's feline attributes such as a two-forked tail.
Startopia has the sirens (winged humanoids) providing (PG friendly) 'love' to a variety of species, from little grey aliens to giant aristocratic slugs.
Most Touhou shipping ends up here since the majority of the characters are various types of youkai. Canonly, Rinnosuke Morichika is the result of a human/youkai pairing, and Keine is half hakutaku (a lion-dog with horns).
League of Legends: human Jarvan and half-dragon Shyvana are...close, put it that way, and Blitzcrank's dating service ships Rammus the armadillo with a cactus (whether it's the one from Plants vs. Zombies remains to be seen).
Relationships between other especies are implied, but rarely explored. In one particular sidequest, a female Homs shows interest in several men, one of them a Nopon, but her interest in him quickly goes away once she realizes just what she's doing.
Xenoblade Chronicles X: Most of the romance in this game is implied rather than explicit, and while there are plenty of interspecies friendships happening, romances seem very rare. The one that we do see involves a human and a Prone, of all things.
It's a bit of a spoiler for this example to be here, but here goes: Catherine can potentially end with this trope, with the human protagonist Vincent and the succubus Catherine hooking up. Subverted in another ending with the same pairing since Vincent becomes a demon too.
Octodad has the eponymous male octopus and his human wife. Their two kids are also human. Just about no one but the Evil Chef (and Big Bad) is actually aware of it. When his wife and son (his daughter apparently already knew) finally find out that he's an octopus, they happily accept him. Though his son does ask how he and his sister were born...
Diablo. YES, THAT DIABLO. It turns out that Sanctuary was created by a few renegade angels and demons who wanted to stop fighting. Their interspecies kids are the humans that make up the Player Characters. The project flopped horribly, with most of the renegades slaughtered by their insane leaders / punished by both heaven and hell, which is why you never see any renegade demons throughout your entire slaughterfest.
Corruption of Champions, it's sister games Trials in Tainted Space and Fall of Eden, and its spin-off sequel Corruption of Champions 2, are all about this. And by romance we mean porking any enemy you beat if your lust meter is high enough, and even then many NPCs are open to sex up to and including a giant turtle womanwho lives in a lake. To be fair though, you can romance companions and lovers if you feel inclined too.
Diddy and Dixie Kong from Donkey Kong Country, not that obvious though: Diddy has a tail which makes him a New World Monkey, while his girlfriend, Dixie, is a chimpanzee.
In the original Plants vs. Zombies, Cactus (female sentient spike-shooting cactus) is said to be dating a nice armadillo in her Almanac entry.
Meanwhile, in the sequel, Dr. Zomboss claims that Chomper has been "getting ultra cozy" with the Bikini Zombie, in a rather transparent attempt to make you distrust Chomper. The premium plant Blooming Heart is also mentioned as being distrusted by her fellow plants because she's apparently "into zombies".
Prince Cornelius was originally a human in love with Velvet, another human, but was cursed into a rabbit-like beast called a Pooka. He initially believes that Velvet can no longer love him in that form, but fortunately it turns out not to be the case and Velvet ends up also becoming a Pooka in the good ending, with them successfully reversing the curse a thousand years later.
Ironically, the same can be said for Velvet's twin brother Ingway. His love interest, Mercedes, is the Fairy Queen of Ringford and he spends most of his time in her company as a frog.
Popolo Crois has The Hero Pietro as the product of one, with a human father (King Paulo) and a dragon mother (Queen Sania). It's lampshaded in the opening of the anime series: a young Paulo pulls a sword out of dragon!Sania's tail, she morphs in her beautiful and tall human form, they smile at each other...
The player character, Mae (who is a cat), used to date a raccoon boy back when she was in junior high; and if the player decides to have Mae crash a college party, she has the option of flirting with a woman nicknamed "Bombshell" (who is a bear).
Guilty Gear has the human Ky who married Dizzy (a Gear). Subverted come Xrd, when it turns out that Ky has become at least a partial Gear.