The Diablo series is loaded with this trope, almost every quest has you off finding a MacGuffin needed to complete a side-quest or to move the plot forward.
Optional sidequests in the first Diablo has you go down into the church labyrinth to find a MacGuffin, (Ogden's Sign, Magic Rock, Anvil of Fury, Black Mushroom+Monster Brain), and then bring it back to the quest-giver NPC in Tristram. One that must always be brought back however, is Lazarus' Staff which is needed to access Lazarus' lair, and always happens to block the access to the final labyrinth level; Diablo's level.
Act 1, To rescue Cain, find the scroll needed to access the Cairne Stones to open a portal to Tristram. Later on, find the Horadric Malus that was left behind in the rogue monastary.
Act 2, To open the door to the final stage requires you to complete a long MacGuffin chain. Find a Horadric Scroll in the sewers, then find the Horadric Cube, then find the two pieces of an ancient staff that must then be put together to form a full staff (The Horadric Staff). Horazon's Journal you need to read in the arcane sanctuary also applies as one even though it's not an item your character can grab.
Act 3, similar to Act 2, to open the door to Mephisto's lair, find the 4 pieces of an ancient flail throughout the Act that must then be put together to form a full flail (Khalim's Will). Act ends with you receiving Mephisto's Soulstone. The optional quests also sends you out to find the Golden Bird, Gidbinn Blade, Lam Essen's Tome MacGuffins.
Act 4, destroy Mephisto's MacGuffin at the nearby Hellforge, but to do it, you need the nearby Hellforge Hammer. The cutscene after finishing Act 4 also shows the player destroying Diablo's MacGuffin.
Act 5, the Relic of the Ancients isn't a MacGuffin you can obtain, but it's plot relevant for Baal to reach the World Stone. Off-camera, Baal's MacGuffin is destroyed as well.
Act 1, To enter the lower levels of the cathedral, find Leoric's MacGuffin in one of the cemetery crypts. Later on, send the player off to locate the three shattered sword pieces of an angel's MacGuffin, but wait... to gain access to one of the rooms that a sword piece is in, you need to side-track and find the two Orbs that will open the door in the nearby forest.
Act 2, Shen's introduction has him finding an item. Then of course there's Zoltan Kulle's long side-tracking task of finding the pieces of his body that must then be put together in his hidden library to make a full MacGuffin. The Act then introduces the Black Soulstone MacGuffin which apparently houses all the souls of the defeated evils from Diablo II. Belial's MacGuffin is then placed in it at Act's end.
Act 3, The Black Soulstone is seen throughout the Act. Once Azmodan's MacGuffin is placed in it at Act's end, the plot behind the Black Soulstone will then start-up the events for the next Act.
Act 4, Diablo itself, is the MacGuffin; being the second rendition of the Black Soulstone.
However, some of them may have some utility. Games as Team Fortress 2 uses Intelligences Briefcases as "flags", meaning that you have to steal the technologic secrets of your enemies.
This may not completely remove it from being a MacGuffin, since an example within the trope page itself is "papers" in spy stories, which usually are implied intel.
In Sonic the Hedgehog, the Chaos Emeralds are almost always the reason anybody does anything at all. In the comics, somebody's always after them. In the games, they aren't always necessary to the plot itself, but regardless, you always need them to get the 'Good' ending.
Every single Tomb Raider game involves Lara on a quest to collect some kind of artifact, except for Unfinished Business.
This trope is sort of subverted in Tomb Raider Legend when the MacGuffin is the legendary sword Excalibur, which Lara uses as a weapon in the final boss fight.
The BMW M3 from Need for Speed: Most Wanted counts as a MacGuffin: the entire career mode is about climbing through the Blacklist until you defeat Razor and recover he took away from you, it's as powerful as a fully tuned Ford Mustang, you only get to use it at the very beginning and at the very end, and also doubles as a Bragging Rights Reward for clearing the game.
Chrono Trigger both uses it straight and subverts it, formerly with the Gate Key (which gets stolen once, but is only mentioned twice in the context of the story as a convenient device to open Time Travel gates. It's subverted with Marle's pendant, which seems to be just as much of a MacGuffin at first, but later becomes vital and useful after its upgrade. Not only is it used to obtain the Cool Ship, but it allows you to open the closed boxes that are scattered everywhere in the game world.
The Chrono Trigger example can be extended to many console RPGs. As soon as the Rebellious Princess or Mysterious Waif joins the party, odds on you'll get their pendant/gem/other valuable heirloom too. The object's relevance varies wildly between actually useful in game (generally opening magical seals or an equippable item), ultimate cosmic plot power, true MacGuffin style object that everyone wants which is actually just junk, mentioned a handful of times in conversation, and an utterly irrelevant item that just clogs up your inventory. Whichever it is, there's no way you'll avoid chasing after the damn thing if it gets lost or stolen.
In fact, the sequel to Chrono Trigger, Chrono Cross, is perhaps an even better example than its predecessor: The Frozen Flame, a mystical artifact which grants its owner ultimate power, is used to drive the plot up until Chronopolis. However, it turns out that instead of an "artifact" it's a giant honkin' rock which is neither frozen nor a flame, and while it does technically posess great power, it requires a huge lab and tons of futuristic equipment to use it. Which, by the way, you don't get to... it appears as a background graphic before a boss battle, and then you never see it again. And then you kick yourself and realize that if you hadn't been chasing the Frozen Flame, you'd be back in your home world, living the idyllic (and very boring from a gameplay standpoint) life you led in the first 15 minutes of the game.
The Seal of Metatron from Silent Hill 3 is a MacGuffin of the Maltese Falcon kind: you have to pound your way through a rotten hospital in Dark Silent Hill to get it, you can't use it during normal gameplay, it's supposed to kill God, and in the end, Claudia says it's just a piece of worthless crap.
The firespawn Blaze in Mortal Kombat: Armageddon has been accused of being a living MacGuffin; the quest to defeat him originally meant to prevent The End of the World as We Know It, but the added side-effect of gaining godlike power inspires the other characters besides those intended on beating him to go after him and provide the basis of the game. As per the nature of the MacGuffin, Blaze's power in relation to whoever defeats him changes with the person, and is never solidly defined.
Finally, Shinnok's Amulet was the MacGuffin for at least three games in the Mortal Kombat series, even though the most we ever learn about it is that it can only be created once (proven false by Quan Chi making a fake one), and that it's used to fuse the Kamidogu (yet another MacGuffin in Deception) and, thus, all of reality together.
The GECK in Fallout 2. It is established as a technological marvel that will solve all your village's problems, but the item itself serves no purpose other than getting you out of the starting area and setting the plot in motion. In fact it is no longer relevant by the time you do find it, and finding it at all is optional.
In Fallout: New Vegas, you're a courier who was attacked for the package he/she was carrying and left for dead in the desert. The main plot is apparently finding the people who attacked you and discovering what was in the package. This MacGuffin actually turns out to be usefulif you pursue either of the two (out of four) endgame questlines that have you siding with either Mr. House (head honcho of New Vegas) or the robot Yes Man.
In The Lonesome Road DLC, it's revealed that the Courier once delivered a similar MacGuffin to the Divide, becoming an Unwitting Instigator of Doom and unfortunately leading it to become the hell-hole it is today.
The Ankaran Sarcophagus from Video Game//Vampire: The Masquerade – Bloodlines; prince LaCroix's obsession with it, and the effect it has on the various vampire factions of the city, drives much of the plot. Subverted in a most satisfying fashion in the anarch and independent endings, where it turns out it contained a bomb planted by your Trickster Mentor intended to kill said prince — even the fact that you were the Unwitting Pawn that allowed the plan to succeed was worth it for the sight of LaCroix opening the casket and finding out what his 'gateway to infinite power' contained...
In Splinter Cell: Pandora Tommorrow, the player character's first mission is to infiltrate an embassy being raided by guerrillas. It's stressed that your objective is to destroy a computer containing sensitive information. Even the hostages being held are of secondary importance. When you contact the man that knows where this information is, he gives you an email he stole from one of his captors and your next objective his to decrypt it. The initial computer you were sent to smash- the one that was so critical it was worth risking the lives of dozens of hostages- is never mentioned again.
The Amulet of Kings in The Elder Scrolls IV: Oblivion. The entire main quest line revolves around getting the Amulet and the Emperor's son to the same place. Once you do, you get to see the ending sequence but not to participate in it.
Isabella in Advance Wars: Days of Ruin is a living MacGuffin. Completely amnesiac except for mysterious knowledge concerning where the protagonists should go next, her return is eventually demanded by the game's Big Bad on pain of aerial bombardment... after which it's revealed that nothing about her is particularly special (since she's a clone); the bastard just wanted to see what would happen if he held the last settlement of man Hostage for MacGuffin.
The entire plot for Threads of Fate involves the main characters questing after the [relic] of ultimate power, capable of granting any wish. It winds up getting transported to another dimension right after the final boss fight, and just short of the opportunity to really begin abusing that sucker's power. C'est la vie.
Kingdom Hearts has the titular kingdom as the MacGuffin of the entire series, since all the organizations are desperately seeking it. Although at first, most of them only know that it's a source of ultimate power, but no one knows for sure what its true nature is. For example, Maleficent thinks it's an actual kingdom, and Ansem The Seeker Of Darkness thinks that it's a realm of purest darkness! It's actually the heart of all worlds. Also, all those hearts freed from The Heartless by the keyblade end up there, collectively taking the form of a heart-shaped moon of immense mystic power. Xemnas and Ansem just exploit phenomena that cause doorways to it to physically manifest. Organization XIII wants to use it to find their hearts and become whole, except for their leader, who wants the power.
The Kingdom Hearts that the Organization had was a synthetic copy made from the hearts freed by the keyblade when it is held captive by an Emblem Heartless. Only Ansem and Master Xehanort came close to obtaining the real Kingdom Hearts and the Kingdom Hearts behind the Door to Darkness was incomplete as not all of the world's hearts have been returned, courtesy of Sora sealing the keyholes of some worlds and Master Xehanort's plan to forge the X-Blade was incomplete, as the complete X-Blade can only be formed by the clashing of 7 lights and 13 darknesses.
The first game also has the seven Princesses of Heart, although the heroes are only concerned with Kairi, who also serves as something of a Macguffin Girl herself (though less so in the second game, where she takes a more active role and is more established) until her actual rescue late in the game, where she actively rescues Sora and then gives Sora a powerful keyblade.
Recent games also introduce the X-Blade as a macguffin, with Kingdom Hearts 3D revealing all the main villians' plots from previous games were attempts to obtain the "materials" to reforge it. Consequently, the series also has a macguffin event: The Keyblade War.
In Monkey Island 2: LeChuck's Revenge, Guybrush Threepwood begins his quest to find the "Big Whoop", a legendary treasure known and craved by all pirates, even when no one knows what it is.
Averted with The Secret of Monkey Island itself. Although mentioned frequently across the series, and the name of the first game, the task of finding it is never used to drive the plot. Guybrush does find it accidentally in the fourth game, but it happens so randomly that the player would never know they found the Secret, if it weren't for the FMV movie named such. The creator of the series still says that he never told anyone what the real secret is, and that he might do a final game to wrap up the series. There are hints that the secret will be that the game events aren't real (i.e., Guybrush is dreaming or is an in-universe fictional character), but it doesn't actually come up.
Planescape: Torment has the Bronze Sphere as its primary MacGuffin. It becomes a Chekhov's Gun if you take it with you throughout the whole game and deduce the identity of the Good Incarnation.
Kane & Lynch: Dead Men features a pair of briefcases early on that Kane and Lynch must try to capture within three weeks to save Kane's family. After finding that one of the cases is missing from its vault, they try and fail to find the last case, and after they're betrayed by The7, they cause a mass jailbreak to get a crew together and continue all the way to Japan to capture the second briefcase. We never discover what's in the briefcases.
The quests, especially open-world leveling quests, in World of Warcraft fall into a small number of broad categories, the most common being 1) talk to someone, 2) kill something (or X number of somethings), and 3) collect something. The Collect-something quests involve MacGuffins. The majority of players don't bother to read quest text in detail; they just check it for the name of the MacGuffins they need to collect this time.
The resonator from Gears of War is an item that supposedly can help deliver a final strike against the Locus Horde by mapping out their tunnels. Midway through the game they activate it, thinking their job is done, only to realize that the resonator didn't do what it was supposed to do. They had to go onto something else to get a map of their tunnels.
The Fire Emblem from the Fire Emblem series takes the form of the local MacGuffin most of the time (the exception being the two Jugdral games, where it is mentioned in one conversation in the ending as a house sigil only).
The eponymous princess from Fat Princess. The game entirely revolves around capturing her, and she does nothing but sit around while one team tries to capture her and another team tries to make her too fat to capture.
The title giving substance of the game Chrome, it's never explained what exactly chrome is, what it does, what it's used for and why exactly it's so valuable, all that's said is that it's of high importance to the plot. In fact you never even get to see it in the game.
The flash game Level Up!lampshades this quite humorously. In the codex, which details everything you encounter and/or do in the game, the magical gems that you need to collect are described thusly: "McGuffin object with mysterious powers and incredible value, considering they are lying around everywhere."
Freespace 2 features the GTVA Colossus, the largest ship ever built. Once deployed, it is treated as a victory condition for any engagement it participates in. The second the Colossus shows up, the enemy either retreats or is destroyed by its beam cannons and fighter compliment, regardless of the enemy fleet's actual strength.
The Colossus is later heavily damaged or even destroyed in a one-on-one engagement to show us how badass the new Shivan juggernaut Sathanas is. Colossus can only survive the engagement if the player destroys all four of Sathanas' forward beam cannons in an earlier mission.
Skies of Arcadia has a Moonstone meteor crash into Shrine Island near the heroes' home of Pirate Isle. Vyse and Aika go ahead and retreive it, but its real purprose is have them off the island so that Valua can turn it into a Doomed Hometown. The Raw Moonstone stays in the inventory for the entire game, but is never used despite being a potential feul source.
The legendary Rogueport treasure in Paper Mario: The Thousand-Year Door. Its only actual purpose is getting Mario and Goombella to meet there and start the investigation about the Door. The treasure is quickly overshadowed by the legendary demon about to break the seal on the Door, and it's never mentioned again until the After The Credits sequence. This is because the legendary treasure was actually a rumor spread by the Shadow Sirens to attract attention to Rogueport and get someone to open the Thousand Year Door. They may or may not have known the seal was going to break on its own anyways though. The fact that there actually was a treasure is a coincidence.
The war plans from the original Castle Wolfenstein. You need to find them while escaping from the castle, but they have no other effect in the game.
City of Heroes police radio missions have dozens of MacGuffins. In the spirit of the trope, exactly which of them is involved in a particular mission is inconsequential; the mission boils down to "Villain group X has MacGuffin Y. Get it back." Sadly, there's not a literal MacGuffin among them, but there is a Plot Device.
One alignment mission hinges on what you decide to do with Steven Werner's precious item. That's the name of the item in question, "Steven Werner's precious item".
Scribblenauts has the Starites. We're never given any explanation to them other than Maxwell's objective is to collect them.
In "unlimited" it's revealed Maxwell does have a reason. At least or that game.
Freelancer has the alien artifact. For 90% of the game, all you know about it is that it keeps getting space stations blown up under Trent's feet.
Dragon Age II Act II has a straightforward MacGuffin; the Qunari "artifact". But the overarching MacGuffin is obscured, it's never an objective for the main characters, yet it impacts the plot more significantly: the lyrium idol.
.hack: The Key of Twilight is a mysterious item told of in legend in every iteration of The World and is the original goal of every group of protagonists. In the Epitaph of Twilight, the Key was required to rouse the Twilight Dragon to fight the Cursed Wave, but the Epitaph was never completed; in series, the Key is considered merely considered to be an item of immense power that can change the rules of the game itself. No one definite thing that could be called the "Key of Twilight" is ever really featured and its recovery tends to go forgotten as its search reveals even greater calamity on the horizon.
The onklunk in Leisure Suit Larry Goes Looking for Love (in Several Wrong Places). It has a piece of microfiche inside which has no real relevance to the game other than a bunch of Dirty Commies who will stop at nothing to get it.
Jiggies are the MacGuffin of the Banjo-Kazooie games. (Except that the Jiggies do open other worlds in the game, making them essential in rescuing Tootie who could be an example of a Living Macguffin...)
The Skull Heart in Skullgirls not only fulfills the purpose of a MacGuffin, the trope is actually referred to by name during Peacock's story.
Peacock to Marie: Some hellish MacGuffin turned you into an undead killing machine and I was created to stop you.
The XJ Unit in Trilby: The Art of Theft. Its purpose is never explained, but the Company are willing to do anything to get it back.
The Blood add-on Cryptic Passage has Caleb heading out to retrieve an ancient scroll, which is, according to the backstory, "capable of upsetting balance of power in the otherworld". That said, the "scroll" might as well be anything else, since it serves just as an excuse for Caleb to shoot his way through new hordes of monsters.
The plot of The Riddle of Master Lu is based around a hunt for the Emerald Seal of the first emperor of China that Master Lu hid in the emperor's tomb. It's a "powerful talisman" that could somehow "be used to unite China under a single dictator". The game is set before the Second World War, and they're afraid of another Hitler or Mussolini. Lu specifically wanted to hide it behind such a riddle that only a mankind united in harmony could uncover it again, but no such luck. Robert Ripley, the Player Character, wants to find it so that it cannot be abused, and unscrupulous villains want to abuse it. Who knows what it does. Sounds like it's magic or something — the story is Magic Realism — but it's not really explained any more than what is said above.
The entirety of Nightmare from the Deep 2: The Siren's Call is spent trying to obtain twelve golden fish tokens needed to open Davy Jones' chest, which contains a conch shell that gives the title siren the power to overcome the villain and his artifact-controlled kraken. Once you actually acquire the shell the game awards you the McGuffin [sic] achievement.