It's been decades since the end of the world as we know it, and Eli (DENZEL WASHINGTON) is a solemn and lone traveler who's spent the past thirty years heading across the remains of America. He's a rarity in being an older, middle-aged man in a time when few of them exist anymore, but he's quite capable of defending himself from the thieves and even cannibals that roam the mostly barren and desolate lands. His source of inspiration is an old book that he carries with him and for which he's on a quest to take it west, although he's uncertain of his exact destination or final reason for his higher-calling journey.
Things become more perilous when he enters a small town, hoping that a local shopkeeper (TOM WAITS) can recharge his old digital music player. While waiting for that and needing water, he enters the tavern across the street where a thug, Martz (EVAN JONES), discovers the hard way that it's best not to mess with him. After dealing with him and an assortment of others, Eli ends up captured by Redridge (RAY STEVENSON) who works for the town's dictator, Carnegie (GARY OLDMAN).
An educated man who remembers the old days before the war and resultant "flash" that opened in the sky and incinerated or blinded most everyone, Carnegie's sole obsession is in finding a certain book that he believes will give him the power to influence and thus rule those in other towns as well. Having seen Eli's prowess and thinking that will come in handy, he hopes to convince him to stay by having Solara (MILA KUNIS) -- the pretty daughter of his blind mistress, Claudia (JENNIFER BEALS) -- spend the night with him.
Eli doesn't fall for that, but does get her to pray with him before eating, and unintentionally allows her to see his valued book, although she can't read, much like everyone else. Her forced description of that, however, alerts Carnegie that Eli possesses the book he so covets, the Bible, but the traveler won't part with it. After he wipes out many of the dictator's thugs who've been ordered to take it from him, Eli continues on his way, not happy that Solara has joined him.
As they continue west, they must not only contend with various locals they encounter -- such as the older Martha (FRANCES DE LA TOUR) and George (MICHAEL GAMBON) -- but also Carnegie and his thugs, including Redridge, Hoyt (JOE PINGUE) and others, who are in hot pursuit of them.