The film opens at Gen Sys, a genetic therapy pharmaceutical company. A female ape (Terry Notary
), designated No. 9 and known as "Bright Eyes" by the staff, has been given the drug ALZ 112, and has shown considerable progress. She is more sociable and calmer than normal apes, and has succeeded in completing the Towers of Hanoi puzzle in 20 moves, which is close to a perfect score of 15. Will Rodman (James Franco
) talks to his boss, Steve Jacobs (David Oyelowo
), and convinces him that he has data to enable them to proceed with human trials for the drug.
The next day, Rodman and Jacobs appear before the board of directors in the Gen Sys conference room. Will explains that the new drug causes neurogenesis, the growth of new brain cells (something that doesn't typically happen after birth) and may heal any number of degenerative brain disorders, such as Parkinson's or Alzheimer's. The only side effect is that the subjects exposed to the drug have a green sparkle to their eyes.
Back in the lab, the senior ape caretaker, Robert Franklin (Tyler Labine
), is having trouble coaxing Bright Eyes out of her cage. She acts aggressively towards Robert and the other helpers. They attempt to lure her out of the cage with orange soda, but when they try to wrangle her with a lasso pole, she goes "ape" and runs rampant through the building. The chase ends when she crashes through the glass window of the conference room and the building's security guards kill her.
Fearing that what they witnessed with Bright Eyes is a violent side effect of the drug, Jacobs pronounces the drug project 'dead.' Will attempts to change his mind, but Jacobs refuses, claiming he wants the remainder of the test apes 'put down.'
After returning to the lab, Robert shows Will a baby ape hidden in Bright Eyes's cell. This explains that their assumption was in error: Bright Eyes was not acting violently because of the drug, but to protect her child. Robert does not have the heart to put down the baby, and gives the task to Will. Unwilling to do so, he decides to take the baby home.
Will returns home, where he lives with his father, Charles (John Lithgow
). Charles suffers from Alzheimer's and needs care from a nurse when Will is not around. Will shows the baby ape to Charles, who soon takes a liking to it. Charles playfully calls the baby Caesar (due to his love of Shakespeare's Julius Caesar
, it is implied).
Caesar soon shows incredible progress, able to feed himself after only 2 days; he has apparently contracted the virus-based ALZ 112 from his mother. His "temporary" residence with Will extends to 3 years and Will sets up a room for him in the attic. Though apelike in some ways, the now half-grown Caesar (Andy Serkis
) is a beloved member of the family and shows great intelligence, communicating complex ideas with sign language.
While Caesar has been showing mental growth, Charles's Alzheimer's is getting worse and he has an altercation with his nurse. Will takes a major risk and steals ALZ 112 from Gen Sys. He gives a dose to Charles, and it appears it is a miracle drug when the next day, Will finds his father sitting at the piano, playing perfectly.
Meanwhile, Caesar has grown enamored of watching the neighbors playing outside, and escapes out the window into their neighbor's backyard. However, his appearance frightens the neighbor's daughter, and her father, Hunsiker (David Hewlett
), angrily attacks Caesar. Will and Charles manage to rescue Caesar, but not before Hunsiker has injured him.
Will sneaks Caesar into a zoo for treatment. Caesar is treated by a veterinarian there named Caroline Aranha (Freida Pinto
). During the procedure, Caroline is fascinated by how well Caesar knows sign language; he even implies through sign language that Will and Caroline should go out to dinner.
To counter Caesar's wanderlust, they take him across the Golden Gate bridge to a redwood forest for some outdoor play time. Upon arriving at the forest, Caesar will not leave Will, but makes a supplication gesture of extending out arm, palm up, which is his way of asking for permission to play. Will gives his permission, and Caesar takes to the trees.
Five years later, Caroline is living as part of the Rodman family and Caesar has grown. Will has even started dressing him in a shirt and pants. During a visit to the forest, Caesar is barked at angrily by a dog, and he counters with a primal cry that scares it off. Will notices that Caesar seems sad and confused about just what he is. They drive past Gen-Sys and Will explains to Caesar about the drug that made him more intelligent, as well as the death of his mother.
In the five years since he was given ALZ 112, Charles' condition has deteriorated. Will reasons that his immune system has developed antibodies and a more aggressive virus is needed. Will takes a risk by going to Jacobs, confessing his secret experiment with his father, and explains that the drug not only repairs cognitive damage but makes people smarter. He says he has reworked the virus and needs Jacobs to approve new animal testing.
Back at home, Charles gets confused and wanders outside and into their neighbor's car. He attempts to drive it, but ends up damaging it. Hunsiker (the same neighbor who attacked Caesar) angrily pulls Charles from the car; in his demented state, Charles is unable to convey his reasons for being there.
Caesar watches this from his window in the attic, and upon seeing the neighbor yelling and angrily pushing Charles, rushes out of the house. He attacks Hunsiker, throwing him to the ground, jumping on him, beating him, and finally biting off a finger. Charles recognizes Caesar, and yells "Caesar, no!" Caesar backs off and goes to Charles. The incident causes Caesar (by court order) to be taken to a primate "'sanctuary" by animal control. Will and Caroline walk him in, and say good bye.
The sanctuary proves to be tough on Caesar during his first days. It is run by John Landon (Brian Cox
), with the care of the animals supervised by his short-tempered and abusive son Dodge (Tom Felton
) and a timid man named Rodney (Jamie Harris
). When Caesar flings his food at Dodge and laughs, the young man angrily responds by turning a fire hose on him, forcing a cowering Caesar into a corner of his cage.
When released with the other animals into the main play area, Caesar meets the alpha male of the group, an ape named Rocket (also Terry Notary
). Rocket tears off Caesar's shirt and beats him. Caesar also takes note of a gorilla named Buck (Richard Ridings
) in a locked cage and an orangutan across from his cage who speaks sign language. Quietly, Caesar begins to communicate with the orangutan, Maurice (Karin Konoval
The sanctuary ships 12 apes to Gen Sys for the testing of the newer version of ALZ 112, which is named ALZ 113. Will is once again in charge of the testing, and chooses a rather harried ape named Koba (Christopher Gordon
) as his first subject. Koba is strapped down and given the new drug through a breathing mask. However, Koba struggles, and the hose comes off the machine. Almost everyone in the lab has their breathing masks on, except Robert, who is accidentally exposed.
That night, Will takes some of the ALZ 113 home to treat his father. Charles refuses the treatment, and dies that night in his sleep. After Will and Caroline pack up the remainder of Charles' belongings, Will's eyes fall on a copy of Julius Caesar.
Some time afterward, Dodge brings some of his friends into the cage area at the sanctuary, where Caesar manages to steal a pocket knife from one of the visitors. Caesar befriends the large gorilla in the yard named Buck, who is never let out of his cage, by letting him loose. Next he releases Rocket, who ventures into the yard. Caesar hits him with a steel gas can. Rocket is ready to fight, but realizes that Buck is loyal to Caesar and will protect him, so he submits. Caesar is now the alpha male. Caesar later lets Rocket out of the cage area and allows him to give stolen cookies (from Dodge) -- one to each ape, bringing solidarity to the group. Caesar has also found a walkway and controls to the windowed enclosure at the top of the play area.
Will returns to work, where he finds that Jacobs has greedily and recklessly pushed the research schedule ahead. While Jacobs is largely thinking of business profits, Will warns him that the major hurdle they need to worry about is how the newer ALZ 113 will affect humans. When Jacobs refuses to listen to Will's warnings, Will quits Gen-Sys. Meanwhile, Robert has been experiencing side-effects from his exposure to the virus, including sneezing that produces droplets of blood from his sinuses.
Will returns to the ape sanctuary and attempts to bribe John Landon into letting him have Caesar. John is willing to do so, but when Will coaxes Caesar to go with him, Caesar refuses.
That evening, Caesar busts out through the window he found and goes back home. He steals ALZ 113 from Rodman's refrigerator and gives it to the apes at the preserve. The next day, John Landon observes the apes having something like a conference. The apes scatter, playing it off. Landon dismisses it as just something weird.
That night, the apes are returning to their cages, but Caesar balks, confronting and 'defeating' Dodge in the yard. When grabbed, Dodge says "Take your stinking paws off me, you damn dirty ape!" Caesar speaks (audibly) for the first time, shouting "NO!" The other caretaker is a witness and runs into the cage area, trying to rescue the now unconscious Dodge.
The apes attack him, but Caesar calls them off and, in a show of mercy, puts him into Caesar's cage. Dodge tries to escape and gets killed. (He is holding a cattle prod and Caesar hits him with the fire hose.)
At dawn, Will calls to check on Caesar but receives no answer. Driving over to investigate, he finds the facilities wrecked, the apes gone, and the ALZ 113 canisters open in the cage areas. He decides to raise the alarm.
Meanwhile, the apes are making their way across town. Caesar divides them into two groups. Buck goes with one group to the zoo to liberate the apes there, while Caesar leads the second group to Gen Sys.
Robert goes to Will's home to talk to him, but Will isn't there and Robert is accosted by Will's short-tempered neighbor, Hunsiker. Startled, Robert sneezes on him. Later on, a woman in Robert's building finds Robert dead.
The news about the ape escape is relayed to Jacobs, who has just made his way to work. He finds that Caesar and the other apes have taken over the building and freed the 12 ALZ 113 test subject apes.
The police are called in. Jacobs boards a police helicopter as Caesar and Buck's groups join forces, now some 50 to 60, chimps, orangutans, and gorillas strong. However, the apes seem to be intentionally preventing the deaths of humans they encounter.
Will and Caroline have heard about the rampage, and upon learning that the apes are headed for the Golden Gate Bridge, they surmise that Caesar is leading the apes to the redwood forest.
The officers are waiting on the bridge to fire on the apes, but Caesar again divides his forces. One group climbs the suspension cables, while another swings from the underside of the structure to get past the blockade.
In the helicopter, Jacobs catches sight of Caesar and orders the men to shoot at him, reasoning that the death of Caesar will call off the others. However, as the helicopter hovers low to the bridge, Buck leaps onto it, bringing it down at the cost of his own life. Caesar feels sadness over the loss of his comrade, and soon finds the remains of the helicopter precariously clinging to the side of the bridge, with Jacobs pleading for help. Instead, Caesar turns away and Koba pushes the helicopter off, killing Jacobs upon impact with the water.
The apes proceed into the forest. Will and Caroline, meanwhile, have made their way onto the bridge. Will steals a police car and heads for the forest. He calls out Caesar's name, but is accosted by one of his followers. However, Caesar soon appears, and the others back away. Will attempts to reconcile with his friend, promising that if Caesar comes home with him, he'll protect him. Caesar shocks Will by holding him close and whispering "Caesar IS home." Will watches as Caesar and several other apes climb up into the trees and survey the forest...and the world beyond.
In an aftermath sequence, we see Will's neighbor Hunsiker reporting for duty as a pilot at San Francisco International Airport. As he walks to his plane, he realizes that he is bleeding from his nose. As the camera pans up, we see the digital boards flashing to different destinations... a sign that soon, these places will be infected with ALZ 113, sealing mankind's fate.
A recurring sub-plot throughout the film is the TV and newspaper reports of a troubled manned Mars probe named Icarus which has become lost in space. What will the astronauts find on their return?