Im going to have to plain out and say Earth Defense Force 2017 is easily one of the pinnacles of game humor. It succeeds in combining brilliant, witty camp with HEAVY satire of almost every shooter out there (and action film). AND it surprisingly has fantastically enjoyable gameplay.
In a close second comes Dungeon Explorer! for the combination of Five Player MP (Yes Five) and the hilarious, and occasionally subtle, parody of rpgs in that era (even some of the gameplay elements are satirical), even while having some of the most insanely difficult bosses ever.
Reeling in at third is Psychonauts, and if you've been reading the thread you've probably figured out why.
Honorable mentions:
TF2, Conker's Bad Fur Day, Black and White, Duke Nukem, And all you crazy big budget games that don't realize how ridiculous you are.
For all you people who include things like Halo 3, and SSBB, please realize that literally everything in existence can have situational comedy, only intentional comedy is actual comedy.