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 desert bandits who try to ambush him. Searching for water, he arrives in a ramshackle town rebuilt 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. Henchmen scour the desolate landscape daily in search of it, but to no avail. Carnegie also has control of a hidden water supply which he rations out to the townspeople.

In town Eli barters with a store owner, the Engineer (Tom Waits), to recharge the battery of his portable music player. While waiting, he goes across the street to the town bar, where a gang of bikers attack, but he quickly kills all fifteen. Realizing Eli is a literate man like himself, Carnegie asks Eli to stay, 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, but he turns her down. While killing time, she finds his book. Unperturbed, Eli offers to share his food with her, and before they eat, he says grace. The following day, Solara repeats the prayer during breakfast with her mother, Carnegie overhears them and realizes Solara's words relate to the book he has been seeking. He soon forces Solara to tell him if Eli was reading a book, and realizes Eli's book is the one he wants—a Bible.

Eli sneaks out of his room and 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 ricocheted shotgun blast. Solara, having left the town, leads Eli to a cave which is 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 reappears 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 thirty years ago. 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 and guided on his journey.

Eventually, Eli and Solara investigate an isolated house. They fall into a trap, but manage to allay the suspicions of the residents, George (Michael Gambon) and Martha (Frances de la Tour), who invite them in for tea. When Eli realizes that the couple are cannibals, they attempt to leave just as Carnegie and his henchmen arrive. In the ensuing shootout, George, Martha and many of Carnegie's men are killed. While Eli and Solara are captured, Carnegie threatens to kill Solara unless Eli surrenders the Bible. With the Bible now in his possession, Carnegie shoots Eli, leaving him for dead. Solara escapes by strangling the driver of the truck she was in and throwing a hand grenade under another truck. She then drives back towards the house to find Eli. Rather than chase her, Carnegie returns to the town, since his sole remaining vehicle is running low on fuel. Solara finds Eli, and they drive until they reach the Golden Gate Bridge, and then row to Alcatraz Island, where they find a group intent on preserving what they can of literature and music. Eli tells the guards that he has a copy of the King James Version of the Bible. Once inside, Eli, 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, the Engineer opens the locked Bible where Carnegie discovers, to his dismay, that it is in Braille, and orders Claudia to read it to him. She pretends that she cannot remember how to read it, telling Carnegie his leg wound has become infected and due to limited enforcers the people have begun to run amok. At the sanctuary, Eli has died, but not before he finished reciting the entire book. The printing press at Alcatraz begins producing copies of the Bible, and Lombardi places one on a bookshelf between the Torah and Tanakh on one side and the Quran on the other. Solara, though offered sanctuary, chooses to return home, taking with her Eli's machete and other possessions.

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