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Following the events of Planet of the Apes, time-displaced astronaut Taylor (Charlton Heston) and the mute Nova (Linda Harrison) are riding on horseback through the desert of the Forbidden Zone. Without warning, fire shoots up from the ground and deep chasms open. Confused by the strange phenomenon, Taylor investigates a cliff wall and disappears before Nova's eyes.
 
Elsewhere in the Forbidden Zone, a second spaceship has crash landed after being sent to search for Taylor and his crew. Like Taylor's ship, it has traveled into Earth's distant future. However, surviving astronaut Brent (James Franciscus) believes he has traveled to another planet. He encounters Nova and notices she is wearing Taylor's dog tags. Hoping Taylor is still alive, he rides with her to Ape City, where he is shocked to discover the simian civilization. He observes the gorilla General Ursus (James Gregory) leading a rally calling for the apes to conquer the Forbidden Zone and use it as a potential food source, against the objections of the orangutan Dr. Zaius (Maurice Evans). Brent is wounded by a gorilla soldier and taken by Nova to the home of the chimpanzees Cornelius (David Watson) and Zira (Kim Hunter), who treat his wound and tell him of their time with Taylor. The humans hide when Dr. Zaius arrives and announces that he will accompany Ursus on the invasion of the Forbidden Zone.
 
Attempting to flee the city, Brent and Nova are captured by gorillas. Ursus orders they be used for target practice, but Zira helps them escape. They hide in a cave which Brent soon discovers is the ruins of the Queensboro Plaza station of the New York City Subway, making him realize that he has traveled through time to Earth's post-apocalyptic future. After following a humming sound deeper into the underground tunnels, Brent begins to hear voices telling him to kill Nova. Entering the remains of St. Patrick's Cathedral, he finds a population of telepathic humans who worship an ancient nuclear bomb.
 
Brent and Nova are captured and telepathically interrogated, and Brent reveals the apes are marching on the Forbidden Zone. The telepaths attempt to repel the apes by projecting illusions of fire and other horrors, as they had done to Taylor and Nova. Dr. Zaius sees through the illusions, however, and leads the ape army to the ruined city. With the apes closing in, the telepaths plan to detonate their "Divine Bomb" as a last resort. They hold a religious ceremony, at the height of which they remove their masks to reveal that they are in fact still-intelligent humans who are descended from survivors of the nuclear wars. The nuclear fallout has mutated them by removing layers of their skin, but greatly increased their psychic abilities.
 
Brent is separated from Nova and taken to a cell, where he finds Taylor. The mutant Ongaro (Don Pedro Colley) uses his telepathic powers to force Brent and Taylor to fight each other to the death. Nova escapes her guard and runs to the cell, screaming her first word: "Taylor!" This breaks Ongaro's concentration, freeing Brent and Taylor from his control. They then overpower and kill him. Brent describes the bomb the mutants worship and Taylor recognizes it as a "doomsday bomb", capable of destroying the planet, marked with the Greek letters Alpha and Omega on its casing.
 
The apes invade the subterranean city, killing Nova and making their way to the cathedral. They are confronted by Méndez (Paul Richards), who raises the bomb into activation position before being gunned down. Brent and Taylor attempt to stop Ursus from accidentally setting off the weapon, but Taylor is shot. Brent manages to kill Ursus before being shot dead by the gorillas. The mortally wounded Taylor pleads with Dr. Zaius for help, but Zaius refuses, saying that man is only capable of destruction. In his last moment, Taylor brings his hand down on the activation switch, triggering the bomb and destroying the Earth. The film ends with a voice-over saying, "In one of the countless billions of galaxies in the universe, lies a medium-sized star, and one of its satellites, a green and insignificant planet, is now dead".