Thirty years after an apocalyptic event, Eli (Denzel Washington) travels on foot toward the west coast of the United States. Along the way he demonstrates atypical but effective survival and fighting skills, hunting strange 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 which was built by and is overseen by Carnegie (Gary Oldman). Carnegie dreams of building more towns and hinges these hopes on finding a certain book. His henchmen scour the desolate landscape daily in search of it.
In the local bar, Eli is set upon by a gang of bikers and kills them all. Realizing that Eli is a literate man like himself, as well as desiring his skills, Carnegie asks Eli to stay, though it is made clear that the offer is non-negotiable. After Carnegie's blind concubine Claudia (Jennifer Beals) gives Eli some food and water, Carnegie asks Claudia's daughter Solara (Mila Kunis) to seduce Eli. Eli turns her down, but invites her to eat with him. Before they eat though, he has her pray with him. The following day Solara prays with her mother. Carnegie overhears them though and forces Solara to tell him that Eli was reading a book. When he asks what kind, she says she does not know, but forms a cross with her two fingers. Carnegie realizes that Eli has a copy of the Bible, the book he has been looking for, as all copies were destroyed after the apocalypse. Eli sneaks out of his room and goes to the store across the street where he asked the Engineer (Tom Waits) to recharge his portable battery. Carnegie attempts to stop Eli, having all his henchmen fire at him, but Eli avoids the gunfire and shoots most of Carnegie's henchmen, even shooting Carnegie's leg with a shotgun blast. After Eli leaves, Solara follows and tracks him down, hoping she can accompany him on his travels and escape the town. Eli agrees on the condition that she take him to the town's water supply. After fulfilling her end of the bargain, Eli traps her there and continues on alone. Solara escapes and soon finds herself set upon by two men. As Solara grapples with the men, Eli suddenly appears and dispatches them with arrows. Eli and Solara continue on until they arrive at a strange house. They stop to investigate and quickly fall into a trap door. The residents Martha (Frances de la Tour) and George (Michael Gambon) appear and invite them in for tea. Eli surmises that they trap, kill, and then eat invaders, evidenced by their shaking hands from too much human meat. Before Eli and Solara can leave though, they are found by Carnegie.
Eli, Solara, Martha, and George hole up inside the house, and George reveals a hidden stockpile of powerful weaponry. A shoot-out ensues, leading to the death of some of Carnegie's men as well as George and Martha. Eli and Solara are captured. Carnegie threatens to kill Solara, which prompts Eli to hand over the Bible. Carnegie shoots him in the stomach and leaves. While in transit, Solara escapes and drives back to help Eli. Carnegie returns to the town as he has the Bible and is low on fuel. Solara picks Eli up and they continue west until they reach the Golden Gate Bridge, then they row to Alcatraz where they find a group of survivors dedicated to preserving pre-war knowledge. Eli tells the guard that he has a copy of the King James version of the Bible, and they are allowed in. Inside they are introduced to Lombardi (Malcolm McDowell), who is the curator of a collection of things from before the apocalypse. Eli, now revealed to be blind, dictates the Bible from memory to Lombardi, before dying from his wounds. Carnegie has the Engineer open the Bible but is distraught to find that it is in Braille, and Claudia refuses to read it to him. His leg has started to go septic, and he will die without ever having read the Bible. Alcatraz begins printing copies of the Bible. Solara is offered sanctuary, but instead chooses to take up Eli's weapons and go back east.