Thanos is usually associated with Captain Marvel and the Silver Surfer, but first appears in the MCU as the mastermind behind the events of The Avengers. He's also considered the archenemy of both Thor and Iron Man, the former case by pursuing the ship carrying the Asgardians (who already had lost their world) to claim the Tesseract (which contained an Infinity Stone), and slaughtering half of them, including Heimdall and Loki, while the latter case revealed him to be Iron Man's Evil Counterpart while Iron Man felt some anger to him over the results of the Battle of New York giving him PTSD. In the comics, Thanos doesn't often fight either of them, although he debuted in The Invincible Iron Man alongside Drax the Destroyer making Iron Man the first superhero he fought so the two being enemies in the MCU counts as an odd example of Hilarious in Hindsight and Older Than They Think.
Played with by Spider-Man: Homecoming. While Vulture is a Spider-Man nemesis in the comics, his main beef in the movie is with Tony Stark, with Spidey just being the guy who keeps getting in his way.
Spider-Man: Far From Home pits Spidey against the Elementals, which are not part of his comic self's usual rogues gallery (though here they are all a Composite Character with other villains who were part of that rogues gallery like Sandman and Hydro-Man). It's a subversion - the Elementals are creations of Mysterio, who is an iconic Spider-Man villain. Like the Vulture before him, Quentin Beck (the ringleader and public face of Mysterio) is driven by his hatred of the late Tony Stark, who (at least in his account) stole Beck's technology, gave it a stupid name, and fired him for being unstable (to which he responds by staging Elemental attacks across Europe), and so Beck transfers his vendetta to Stark's protege, Peter Parker.
Ant-Man and the Wasp features both the Ghost and Sonny Burch as villains. Both of them were Iron Man villains in the comics, though the former got an Adaptation Origin Connection to the MCU version of Egghead, normally a villain of Hank Pym's Ant-Man to justify her inclusion.
Taskmaster is the main villain of Black Widow (2021). Though it's true that Taskmaster is treated as a general Marvel villain who antagonizes anyone for a paycheck (including the Avengers, Captain America, Iron Man, Ant-Man, Spider-Man, Deadpool, X-Men...), he's never been a personal antagonist to Black Widow although S.H.I.E.L.D., who she has worked for at times, does occasionally have run ins with him.
The real Mandarin appeared in Shang-Chi and the Legend of the Ten Rings, despite Shang-Chi only having dealt with the Mandarin in one non-canon comic and the latter traditionally being Iron Man's Archenemy. The reason for this is twofold: Firstly, Marvel no longer has the rights to Shang-Chi's traditional nemesis, his fatherFu Manchu (on whom the Mandarin was arguably based in the first place), meaning a new antagonist was needed for the film. Secondly, Marvel Studios was under the impression that the Mandarin's traditional depiction as an Asian villain antagonizing an American White Male Lead such as Iron Man, while acceptable when they were created back in the 1960s, would be controversial with 21st century audiences. However, by having the Mandarin fight Shang-Chi — the MCU's first Asian lead — Marvel sought to avoid these perceived Unfortunate Implications. A fake Mandarin was set up as a decoy main villain to Big Bad Aldrich Killian in Iron Man 3, though the latter's dragon tattoos make him a Composite Character with the Mandarin from the comics to acknowledge the original connection, but the fact that Iron Man died in Avengers: Endgame probably helps allow the real one to eventually fight Shang-Chi. The movie also features a second example, as Shang-Chi ultimately must face the Dweller in Darkness, traditionally an enemy of Doctor Strange and Thor, during the final battle.
General Thaddeus "Thunderbolt" Ross starts out antagonizing Bruce Banner/Hulk much like in the comics, but once he appears again in later movies he becomes an obstacle for the Avengers as a whole, especially Captain America, often serving as theObstructive Bureaucrat of the MCU. Shang-Chi and the Legend of the Ten Rings also brings back classic Hulk villain Abomination, who hadn't been seen since he fought Hulk in The Incredible Hulk, for a cage match against Doctor Strange's ally Wong.
Spider-Man: No Way Home has an odd variation - while all of the villains are indeed Spider-Man foes (Green Goblin, Doctor Octopus, Sandman, the Lizard and Electro), they are visitors from alternate universes that fought differentversions of Spider-Man before facing off against the MCU version of the character. Lampshaded when Doctor Octopus unmasks Spider-Man and immediately realizes the boy is not his world's Peter Parker.
Doctor Strange in the Multiverse of Madness features Gargantos, an extremely obscure monster that fought Namor. That said, it's commonly believed to be a stand-in for an actual Dr. Strange villain, Shuma-Gorath, due to potential rights issues with Robert E. Howard's Kull stories where the name first appeared. Gargantos is also a lot weaker than Shuma-Gorath would be, simply being a monster minion for Strange and Wong to kill early on.
Ant-Man and the Wasp: Quantumania features Kang the Conqueror, usually an enemy of the Avengers (with no specific connection to Scott Lang), as the villain; though part of the idea here is to lay groundwork for him to become a threat to the Avengers in future films. M.O.D.O.K., another major adversary of Captain America and Iron Man (known in the comics as the founder of AIM, established in the MCU by Aldrich Killian), also appears, though his true identity as Darren Cross is an actual Ant-Man foe, being the first Ant-Man film's villain.
The High Evolutionary serves as the main antagonist of Guardians of the Galaxy Vol. 3, with a particularly personal connection to Rocket, whom he created. In the comics, he and Rocket have no connection, nor is he particularly associated with any one particular hero or group in an antagonistic role, being a more morally grey character than the film version. He first debuted in the pages of Thor, and has connections to everyone from Adam Warlock to Spider-Woman to the Werewolf by Night to Quicksilver and the Scarlet Witch.
Agents of S.H.I.E.L.D. makes liberal use of this trope since most of the main characters are Canon Foreigners, and thus have no existing rogues from the comics. You have enemies of Iron Man (Blizzard, (a) Whiplash), Thor (the Absorbing Man, Lorelei), Captain America (the Watchdogs), the Hulk (General Talbot), the Avengers (Graviton) (these two eventually become a Composite Character), and even Nova (Blackout). Special mention goes to Mister Hyde, who has bounced around between multiple superheroes in the comics but is here made specifically a S.H.I.E.L.D. villain by capitalizing on the development in the comics that his daughter is a S.H.I.E.L.D. agent. Lash and Eli Morrow could also qualify, respectively being an Inhumans and an All-New Ghost Rider villain transplanted to S.H.I.E.L.D., but then again Inhumans and Ghost Rider himself were used in the show so they fit (special mention to Lash becoming the Superpowered Evil Side to Melinda May's ex Dr. Garner).
Agent Carter likewise stars someone who in the comics was merely a supporting character and had no specific enemies of her own. The show's villains were Dr. Faustus and the Secret Empire (renamed the Council of Nine in this show) from Captain America, Madame Masque from Iron Man, and an evil Black Widow, who is technically a Canon Foreigner but draws on the heroic Black Widow's backstory that she wasn't the first such Soviet agent.
Daredevil season 3 features Rosalie Carbone as one of the supporting antagonists. In the comics, she was a Punisher villain who hooked up with Frank Castle (who was using an assumed name). Here, she's not remotely affiliated with the Punisher at all, instead making her debut in the last two episodes of Luke Cage season 2, before taking a prominent role in Daredevil.
Jessica Jones features Kilgrave as its main antagonist. Kilgrave started as a Daredevil villain. It becomes ironic when Jessica meets Claire Temple and she offers to solicit Matt to help out in Jessica's crusade against Kilgrave. She turns down the offer because she doesn't want him enslaved as well, but in the comics, he's able to resist Kilgrave's commands due to his Disability Superpower. Will Simpson, in the comics a Daredevil villain known as Nuke, also appears as an enemy of Jessica's (and the former boyfriend of her friend Trish Walker), albeit with a very different background and origin.
Luke Cage: The second season introduced Tilda Johnson aka Deadly Nightshade as the daughter of Mariah Dillard. In the comics, not only is she in no way related to Black Mariah, but she was introduced as a Captain America villain.
Iron Fist features the Hand as main antagonists, who are usually Daredevil foes just like Kilgrave, but the difference is that Matt did actually fight them in season 2 of Daredevil beforehand. Not only does Danny square off against the Hand in the show, but it turns out the Hand are the sworn enemies of K'un L'un denizens and it's the Iron Fist's duty to oppose them. Similarly, Typhoid Mary appears as an antagonist in the second season of Iron Fist, despite her being more associated as one of Daredevil's rogues. Justified in Typhoid Mary's case: since Matt is presumed dead after the events of The Defenders, Danny's fighting her since she's one of those foes that would normally be one for Matt to fight.
The true villain of Loki is ultimately revealed to be Kang the Conqueror, or rather various alternate counterparts of him. The first season has a Composite Character taking aspects of Immortus and He Who Remains, while other versions are teased for future seasons. In any incarnation, Kang is mostly an Avengers villain and does not have any particular connection to Loki in the comics.
The series sees Clint Barton and Kate Bishop face off against Maya Lopez, a.k.a. Echo, who was initially introduced in the comics as an enemy (later ally) of Daredevil who fought him after he was framed for the murder of her father. The show changes Maya's target from Daredevil to Hawkeye, whom she believes killed her dad during his time as Ronin. Her presence in the series is somewhat justified through the fact that both Echo and Hawkeye have used the Ronin alias.
In the comics, Jacques Duquesne, a.k.a. the Swordsman, was an Avengers villain and Clint's Evil Mentor specifically. In the TV show, Duquesne has absolutely zero connection to Clint, and is instead played up more as Kate's adversary since he's her mom's suspicious fiancée. Ultimately subverted, however, as it's revealed near the end of the season that he's completely innocent despite seeming shady.
The Wham Shot at the end of Episode 5 reveals that Maya's mysterious employer is The Kingpin, another villain mostly associated with Daredevil (and Spider-Man) in the comics. He's included in the show not because he's tied to one of the Hawkeyes in the comics (because he isn't), but because he's tied to Maya.
A major subplot in the latter half of the season involves Clint being targeted for death by Yelena Belova, originally an enemy of Black Widow. As a result of the MCU giving her a major case of Adaptational Heroism, Yelena instead hates Clint due to wrongly thinking he was responsible for Black Widow's death. Yelena also clashes with Kate, but makes it clear that she has no desire to hurt her, and generally comes off as more of a Friendly Enemy whenever the two interact.
Ms. Marvel's villains are (loosely) based on the Destine family from ClanDestine, who aren't villains and haven't been seen in the comics since before Kamala Khan was even created. They were repurposed for Ms. Marvel because the show deals with Kamala's cultural identity as a Pakistani-American Muslim, and the Destines are half-genies and therefore fit within Middle Eastern mythology.
Unfortunate Implications. A fake Mandarin was set up as a decoy main villain to Big Bad Aldrich Killian in Iron Man 3, though the latter's dragon tattoos make him a Composite Character with the Mandarin from the comics to acknowledge the original connection, but the fact that Iron Man died in Avengers: Endgame probably helps allow the real one to eventually fight Shang-Chi. The movie also features a second example, as Shang-Chi ultimately must face the Dweller in Darkness, traditionally an enemy of Doctor Strange and Thor, during the final battle.