My Name is Earl features Earl Hickey (Jason Lee), who spent his whole life being a second-rate criminal, until one day he won the lottery, only to be hit by a car and lose the ticket. While in the hospital, Earl saw a show about Karma, decided that was the problem in his life, and made The List, writing down everything he ever did wrong to someone else. He sets off to right these wrongs, aided by his brother Randy (Ethan Suplee). Karma smiles on him, and he finds his missing lottery ticket.

Earl and Randy try to find the people that Earl has wronged and figure out how they can make it up to the person. Zany characters in their lives include Earl's ex-wife Joy (Jaime Pressly) and her new husband Darnell, a.k.a Crab Man (Eddie Steeples), plus hotel maid and dancer Catalina (Nadine Velazquez). Then there are the secondary characters such as Patty the daytime hooker and TV's Tim Stack (playing himself as a washed up alcoholic).

Earl's list provides a seemingly endless list of wrongs waiting to be righted, each getting Earl and Randy into another crazy situation. You can tell by the items on the list (stole a one-legged woman's leg) just how much the guys have changed.