It draws inspiration from the original Mutant League Football, as well as other games in the genre such as NFL Blitz.

The game features 7-on-7 action, with teams made up of various mutants, namely Skeletal Deadheads, Monstrous Orcs, BruiserBots, Mutant-Humans, Hell-Spawned Demons, Rampaging Werewolves, and Criminal Aliens.

Players can call normal plays, as well as "dirty tricks", which include bribing the referee, using a chainsaw to cut through the opposition defense, and rigging the ball with a bomb.

Many players likewise have humorous names spoofing real-life current and former NFL players, such as Bomb Shady, Von Killer, Wham Neutron, Throb Bronkowski, Hatrick Myhomies, Ratspew Splattered, Cooper Pup, and Airbourne Dodgers.

In early 2022, Digital Dreams Entertainment announced Mutant Football League 2.