Thirty years after a nuclear apocalypse, Eli (Denzel Washington) travels on foot toward the west coast of the former United States. Along the way he demonstrates uncanny survival and fighting skills, hunting wildlife and swiftly defeating a group of highway bandits who try to ambush him. Searching for a source of water, he arrives in a ramshackle town built and overseen by Carnegie (Gary Oldman). Carnegie dreams of building more towns and of controlling the people by using the power of a certain book. His henchmen scour the desolate landscape daily in search of it, but to no avail.
In the local town bar, a gang of bikers attacks Eli, but he kills them all. Realizing Eli is a literate man like himself, Carnegie asks Eli to stay, although making it clear that the offer is non-negotiable. After Carnegie's blind mistress Claudia (Jennifer Beals) gives Eli some food and water, Carnegie orders Claudia's daughter Solara (Mila Kunis) to seduce Eli. Eli turns her down, but she discovers he has a book in his possession. Eli offers to share his food with her. Before they eat, though, he has her pray with him. The following day, Solara prays with her mother. Carnegie overhears them and realizes Solara's words may relate to the book he has been seeking. He forces Solara to tell him Eli was reading a book. When he asks what kind, she says she does not know, but forms a cross with her two index fingers. Carnegie realizes Eli has a copy of the Bible, the book he wants. Eli sneaks out of his room and goes to the store across the street, where he had earlier given the Engineer (Tom Waits) his portable music player to recharge the battery.
Carnegie has his henchmen shoot at Eli, but the bullets seemingly just graze him, as if he is being protected. Eli shoots most of Carnegie's men and hits Carnegie in the leg with a shotgun blast. Solara leads Eli to the town's water supply, hoping she can accompany him on his travels. Eli traps her inside and continues on alone. Solara escapes and soon finds herself ambushed by two bandits who attempt to rape her, but Eli appears and kills them.
As they continue on, Eli explains his mission to Solara . According to Eli, his book is the last remaining copy of the Bible, as all other copies were intentionally destroyed following the nuclear war. He says he was led to the book by a voice in his head, which then directed him to travel westward to a place where it would be safe. The voice assured him that he would be protected on his journey. Thus, for the last thirty years he has been traveling west, guided by his faith.
Eventually, Eli and Solara investigate an isolated house. They fall into a hidden pit, but manage to allay the suspicions of the residents, Martha (Frances de la Tour) and George (Michael Gambon), who invite them in for tea. When Eli realizes that the couple are cannibals, they attempt to leave, but then Carnegie and his posse arrive. In the ensuing shootout, George, Martha and some of Carnegie's men are killed. Eli and Solara are captured. When Carnegie threatens to kill Solara, Eli gives him the Bible. Carnegie shoots him, and leaves him for dead.
Solara escapes and drives back to help Eli. Rather than chase her, Carnegie returns to the town since his sole remaining vehicle is running low on fuel. Solara picks up Eli. They drive until they reach the Golden Gate Bridge. They then row to Alcatraz, where they find a group intent on saving what they can of civilization. Eli tells the guards that he has a copy of the King James version of the Bible. Once inside, Eli, who is revealed to be blind, begins to dictate the Bible from memory to Lombardi (Malcolm McDowell), the leader of the group.
Meanwhile, back in the town, Carnegie opens the locked Bible, but discovers that it is in Braille. He orders Claudia to read it to him, but she refuses. Carnegie's leg wound has become septic, and he realizes he is going to die. Order breaks down, and the residents start looting.
Eli dies, but not before he has finished reciting the Bible. The printing press at Alcatraz begins making copies of the New King James Version of the Bible. Lombardi places one on a bookshelf between the Torah and Tanakh on one side and the Qur'an on the other. Solara, though offered sanctuary, chooses to head back home, taking with her Eli's possessions.