The first major role Suplee landed was as Willam in Mallrats, directed by Kevin Smith, alongside future My Name is Earl costar Jason Lee.

At the same time as the filming of Mallrats, Suplee also had a recurring role as Frankie "The Enforcer" Stechino in Boy Meets World, from 1994 to 1998.

Suplee's dramatic performances include the roles of the ruthless white power skinhead Seth in American History X, one of three men who rape a clown in Vulgar, Ashton Kutcher's goth college roommate "Thumper" in The Butterfly Effect, American football player Louie Lastik in Remember the Titans, Johnny Depp's buddy and initial drug-dealing partner Tuna in Blow, and the simpleminded Pangle in Cold Mountain.

In 2014, he was cast in the TV Land original sitcom Jennifer Falls, which reunited him with My Name Is Earl co-star, Jaime Pressly.

[4] In 2016, Suplee started playing D in Hulu's series Chance, as well as police officer Billy "Beer Pong" Tompkins on the Netflix sitcom The Ranch.