Each M.U.G.E.N series and game has a main boss for the heroes to fight.
- Let's get this out of the way first: Any character who was a Big Bad in their home game is more than likely usable in this game, usually in the same role (i.e. M. Bison or Shao Kahn).
- Suave Dude in the original M.U.G.E.N and Kung Fu Man Pack, as he's the one who kidnapped Kung Fu Man's girlfriend and set all the other characters loose to attack him.
- Prince Janos in The Black Heart
- Thanoseid in the DC & Marvel Pack.
- Kiyoko Yoshimura, Atsuhiro Tomioka and Gen Urobuchi in the Original Generation Pack.
- Various SNK Bosses in the Another King of Fighters series.
- Gustav Munchausen & his The Dragon Psyqhical Lorien in The King of Fighters Memorial Level 1.
- Element in The King of Fighters Memorial Level 2.
- Meimu in Touhou Gensokyo Reloaded.
- Saint Not! in Saturday Mornin Mayhem.
- Befitting the game's original inspiration, the Phoenix Force acts as the final boss of the Avengers vs. X-Men game. Upon defeat, it splits apart and possesses Cyclops, Colossus, Emma Frost, Namor and Magik, turning them into the Phoenix Five as per canon.
