Larry Daley just can't keep hold of a steady job, but he begins to think there may be hope at last as he is hired as a night security guard at the Museum of Natural History. Everything goes well on the first night for him. That is until the exhibits start to come to life after the sun sets. He now has a choice to make. He can either continue on finding another job or manage the exhibits.

Larry Daley joins forces with Teddy Roosevelt, Amelia Earhart and others to prevent one of history's worst villains from conquering the world.

At the Museum of Natural History, there's a new exhibit being unveiled. Larry Daley, who manages the night exhibit where the exhibits come to life because of the Tablet of Ahkmenrah, is in charge of the presentation. But when the exhibits go awry, Larry finds himself in trouble. He learns the Tablet is corroding so he does some research and learns that Cecil, the former museum guard, was at the site when the Tablet was discovered. He tells Larry they were warned if they remove it could mean the end. Larry realizes it means the end of the magic. He talks to Ahkmenrah who says that he doesn't know anything. Only his father the Pharaoh knows the Tablet's secrets. He learns that the Pharaoh was sent to the London museum. So he convinces Dr. McPhee, the museum curator, to help send him to London. He takes Ahkmenrah with him but some of the others tag along, like Teddy Roosevelt, Attila, Octavius, and Jedediah.