A female ape, designated No. 9 (aka "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 (Franco) talks to his boss, Steve Jacobs (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 at Gen-Sys' conference room. Will explains that the new drug causes neurogenesis, which allows the brain to grow new brain cells (something that doesn't happen after birth) and 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 the eyes.
Back in the lab, the senior ape caretaker named Robert Franklin (Labine) is having trouble coaxing Bright Eyes out of her cage, acting 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 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 is currently suffering 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 (implied from his love of the Shakespeare play).
Caesar soon begins to show incredible progress, able to feed himself after only 2 days, and the temporary caring for him soon pushes on to 3 years, with Will setting up a room for him in the attic his home. Though apelike in some areas, Caesar also has become domesticated. He can communicate through sign-language, and communicate complex ideas and statements.
While Caesar has been showing mental growth, Charles has been showing signs that his Alzheimer's is getting worse when he has an altercation with the nurse. Will then takes a major risk, and steals ALZ 112 from Gen-Sys. Giving some to Charles, 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 (David Hewlett) angrily attacks Caesar. Will and Charles manage to rescue Caesar, but not before the father has injured him.
Will then sneaks Caesar into a local zoo for treatment. Caesar is treated by a veterinarian there named Caroline Aranha (Frieda Pinto). During the procedure, Caroline is fascinated by how well Caesar knows sign-language, and that he even implies through sign-language that both Will and Caroline should go out to dinner.
To counter Caesar's wanderlust, they take him across the golden gate bridge to the 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 now living as part of the Rodman family, and Caesar has grown as well. 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. Will and Caroline drive past Gen-Sys, and Will explains to Caesar about the drug that made him more intelligent, as well as his mother having died.
In the 5 years since he was given ALZ 112, Charles' condition has deteriorated. Will reasons his immune system has developed antibodies and a more aggressive virus is needed. Will takes a risk by going to Jacobs, confessing about his secret experiment with his father, and explains that the drug not only repairs, 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. The neighbor (the same one who attacked Caesar) angrily pulls Charles from the car, but Charles is unable to convey his reasons properly due to his deteriorating mental condition.
Caesar sees this from his window in the attic, and upon seeing the neighbor yelling and angrily pushing Charles, rushes out of the house. He attacks the neighbor, throwing him to the ground, jumping down on top of 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 a man named 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 firehose on him, 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 groups, an ape named Rocket. Rocket tears off Caesar's shirt, and beats him. Caesar also takes note of a gorilla in a locked cage named Buck, and an orangutan across from his cage that speaks sign-language. Quietly, Caesar begins to communicate with the orangutan, Maurice.
The sanctuary also 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. The new subject is strapped down and given the new drug through a breathing mask. However, Koba struggles, and the hose comes off the machine. Almost everyone has had 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 help 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, where Caesar manages to steal a pocket knife from one of the visitors. Caesar then befriends the large gorilla in the yard named Buck, who is never let out of his cage, by letting him loose. He then releases Rocket, who ventures into the yard. Caesar hits him with a steel gas can. Rocket is ready to fight, but realizes that the 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 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 pushed the research schedule ahead recklessly. 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, with the result being blood from his sinuses when he sneezes.
Will then returns to the preserve where he attempts to Bribe John Landon into letting him have Caesar. John is willing to do so, but when Will attempts to coax 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 tries to call to check on Caesar, but receives no answer. Driving over to investigate, he finds the facilities wrecked, the apes gone, and he ALZ 113 canisters on in the cage areas. He decides to raise the alarm.
Meanwhile, the apes are now making their way across the town. Caesar then designates that they split into two groups. Buck is sent with some apes to the zoo to liberate the other apes, while Caesar goes with another group to Gen-Sys.
Meanwile, Robert has gone to Will's home to talk to him, but is accosted by Will's short-tempered neighbor. Startled by him, Robert accidentally sneezes on him. Later on, a woman in Robert's building finds him dead.
The news is relayed to Jacobs, who has just made his way to work. Upon entering the building, 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, and Jacobs boards a police helicopter as Caesar and Buck's group rejoin forces, now some 50-60 apes, 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 hearing that the apes are headed for the Golden Gate Bridge, surmise that Caesar is leading the apes to the Red Oak Forest.
The officers are waiting on the bridge to fire on the apes, but Caesar then has his forces split up into two groups: one begins climbing up the suspension cables, while another swings from the underside of the structure to get past them.
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 the helicopter, bringing it down, but at the cost of his own life. Caesar feels sadness over the loss of one of his comrades, 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, with Jacobs dying upon impact of the water.
The apes proceed into the forest. Will and Caroline meanwhile, have made their way onto the bridge. Will manages to steal 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 then shocks Will by holding him close, and audibly whispering to him in a spoken voice, "Caesar IS home." Will then 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?