In a post-apocalyptic 2043, a lone hero, Eli (Denzel Washington), guards the Book of Eli, which provides knowledge that could redeem society. The despot (Gary Oldman) of a small, makeshift town plans to take possession of the book.

Andy is departing for college, and his toys, including Woody (Tom Hanks) and Buzz (Tim Allen), are going to be put in the attic. Before they can be put in the attic, they are accidentally thrown away and are picked up by the garbage men. The toys find themselves at a local day-care center, where they must try to survive the playful but careless pre-school children. Woody attempts to save his friends and find themselves a new home, but matters are further complicated when Buzz is damaged during an escape attempt. The toys try to reset Buzz, but end up causing him to revert to a Spanish version of his delusions of being a space ranger, much to Jessie's delight and the other toys' discomfort.

A global cataclysm leads to the end of the world and has survivors struggling for their lives, while a US government agency called the "Institute for Human Continuity" attempts to use ships to ensure the survival of the human race.

The movie centers on a young couple, Katie and Micah, who are haunted by a supernatural presence in their home. The movie is presented through the camera set up by the couple to capture the paranormal activity.