Back in the day, Lazarus (Samuel L. Jackson) sang and played the blues on his guitar at Bojo's Juke Joint in a small town outside of Memphis, Tennessee. Now he lives as a God-fearing, broken, and bitter man with a cheating wife who runs off with his brother. His soul is lost and he feels betrayed. It seems the majority of people in the town are a little down and out.

In this poor community, whites and blacks are barely getting by in life, until one night Lazarus comes across a young white woman, half-naked and beaten unconscious, whose name is Rae (Christina Ricci). She's been left for dead on the side of the road. The God-fearing, middle-aged black man Lazarus quickly learns that this woman, who needs nursing back to health, has a peculiar sexual disorder. He realizes when her so-called fever hits that Rae's problem is nymphomania. It has to do more with love lost than any found.

Raped as a child, abandoned from the love of her mother, used and abused by every man in town, Rae's only real hope was her boyfriend Ronnie (Justin Timberlake), but Ronnie wasn't quite stable either. He suffers from severe anxiety. He decides in desperation to enter the Army in hopes of providing a better life for them both. When Ronnie has to go off to boot camp, Rae is left alone and the fever hits her. In desperation she reverts back to surviving the only way she knows how, by giving any man what he wants to get what she needs.

A major player in her wants is a beefy, drug-dealing black man named Tehronne (David Banner), who supplies her with drugs. After a wild sex party with her friends, she is beaten and tossed on the road by a trusted buddy of Ronnie. It's a good thing Lazarus found her.