Will Rodman, a pharmaceutical chemist at the San Francisco biotech company Gen-Sys, is testing the viral-based drug ALZ-112 on chimpanzees to find a cure for Alzheimer’s disease. ALZ-112 is given to a chimp named Bright Eyes, greatly increasing her intelligence. However, during Will’s presentation for the drug, Bright Eyes is forced from her cage, goes on a rampage and is shot to death. Will’s boss Steven Jacobs terminates the project and has the chimps euthanized. However, Will’s assistant Robert Franklin discovers that the reason for Bright Eyes’ rampage was that she had recently given birth to an infant chimp. Will reluctantly agrees to take in the chimp, eventually giving him the name “Caesar.” Will learns that Caesar has inherited his mother’s intelligence through being exposed to ALZ-112 in her womb, and decides to raise him. Three years later, Caesar has become a highly intelligent animal due to the ALZ-112, and is able to play games, draw pictures, and communicate with Will through sign language. Will soon introduces Caesar to the redwood forest at Muir Woods National Monument. Meanwhile, Will treats his dementia-suffering father Charles Rodman with ALZ-112, which seems to restore his cognitive ability.
Five years later, when Caesar reaches adolescence and sees a dog on a leash like his own, he questions his identity and learns of his origins from Will. Meanwhile, Charles’ condition returns as his immune system becomes resistant to ALZ-112. Caesar injures an aggressive neighbor, Douglas Hunsiker (a man who tried to kill Caesar when he was a few years old), while defending a confused Charles from him. As a result, he is taken from Will by animal control placed in a primate shelter. Due to his increased intelligence and his different appearance to the other apes, Caesar is often tormented by the alpha chimp named Rocket and the chief guard, Dodge Landon. However, Caesar also befriends a former circus orangutan named Maurice, who also knows sign language. Caesar learns how to unlock his cage, gaining free access to the common area. With the assistance of a gorilla named Buck, he confronts Rocket and claims the position of alpha chimp. Meanwhile, Jacobs clears the development of a more powerful, gaseous version of the drug – ALZ-113 – when Will tells him it can also improve intelligence. Will takes the drug home to try to save his father, but Charles declines further treatment and dies overnight.
After attempting to test the drug on a scarred bonobo laboratory test subject named Koba, Franklin becomes exposed to ALZ-113 and becomes ill. Attempting to warn Will at his home, he sneezes blood onto Hunsiker and is later discovered dead. Will attempts to reclaim Caesar, but Caesar refuses to go home with him. Instead, he escapes from the facility later at night and returns to Will’s house, where he takes canisters of the ALZ-113. Upon returning, Caesar releases the gas and allows it to enhance the intelligence of the other apes in the sanctuary. When Dodge attempts to get him back into his cage, Caesar speaks for the first time, shouting “No!” and gets into a fight with Dodge while freeing the apes, which inadvertently leads to Dodge’s death. The apes flee the facility, releasing Koba and the remaining apes from Gen-Sys, and free more apes from the San Francisco Zoo.
A battle ensues as the ape “army” fights their way past a police blockade on the Golden Gate Bridge in an attempt to escape into the redwood forest. Buck sacrifices himself to save Caesar by jumping into a police helicopter in which Jacobs is riding: Koba pushes Jacobs into the Golden Gate strait to his death after the crash. As the apes find their way into the forest, Will catches up to them in a stolen police car and warns Caesar that the humans will hunt them down and begs him to return home. In response, Caesar hugs him and says, “Caesar is home”. Will, realizing that this is indeed their last goodbye, respects Caesar’s wishes. The apes embrace their new lifestyle in the forest as news and police helicopters fly over San Francisco.
In a mid-credits scene, Hunsiker leaves his house for work as an airline pilot, arriving at San Francisco International Airport for his flight to Paris. It is revealed that he is infected with ALZ-113 as his nose begins to drip blood onto the floor. A graphic then traces the spread of the virus around the globe via international flight routes.