Knucklehead follows a con artist named Eddie Sullivan (Mark Feuerstein). After incurring a large debt with a local criminal ringleader, Eddie creates a get-rich-quick scheme and enlists a sweet gentle giant named Walter (Paul Big Show Wight) as his unwitting accomplice. Walter's orphanage, the only home he's ever known, also needs funds desperately. Upon overhearing Walter's predicament, Eddie convinces the no-nonsense head nun, Sister Francesca (Wendie Malick), that Walter can win the money as a fighter and pay off the church's debts. Eddie's plan: travel from town to town with Walter and enter small, unsanctioned fighting competitions for prize money
Sister Francesca dispatches Mary (Melora Hardin) as a chaperone for both Walter and the money and gives Eddie a week, and a prayer, to make it happen. During their journey across the south to the annual Pro-Am MMA tournament in New Orleans, Walter discovers what life is like outside the orphanage, while Eddie becomes morally conflicted over whether to take all the loot for himself or keep his promise to Walter, the one person he can actually call a friend.