Thomas, Twilight, and the Rise of the Planet of the Apes is the first upcoming Thomas/MLP:FIM/Planet of the Apes crossover made by Hiatt Grey.
Will Rodman, a scientist 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. But then, during Will's presentation for the drug, Bright Eyes is forced from her cage, goes on a rampage, and is killed. 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 agrees to take in the chimp, who is named Caesar. Will learns that Caesar has inherited his mother's intelligence and decides to raise him. Three years later, Will introduces Caesar to the redwood forest at Muir Woods National Monument. Meanwhile, Will treats his dementia-suffering father Charles 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's condition returns as he becomes resistant to ALZ-112. Caesar injures a neighbor, Douglas Hunsiker, while defending a confused Charles. As a result, he is placed in a primate shelter where he is treated cruelly by a chimp named Rocket and the chief guard, Dodge Landon. Caesar learns how to unlock his cage, gaining free access to the common area. With the assistance of a gorilla named Buck, he confronts the sanctuary's alpha, Rocket and claims that position. Meanwhile, Jacobs clears 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 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 the chimp refuses to go home with him. Instead, he escapes from the facility 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. When Dodge attempts to get him back into his cage, Caesar speaks for the first time, yelling "No!" and then electrocuting him to death. The apes flee the facility, release the remaining chimps 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 to escape into the redwood forest. Buck sacrifices himself to save Caesar by jumping into the helicopter in which Jacobs is riding. The helicopter crashes onto the bridge, trapping Jacobs in the wreckage. Jacobs is then killed by Koba. As the apes find their way into the forest, Will arrives and warns Caesar that the humans will hunt them down, and begs him to return home. In response, Caesar hugs him and says that, "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.
In a mid-credits scene, an infected Hunsiker leaves his house for work as an airline pilot, arriving at San Francisco International Airport for his flight to Paris. His nose begins to drip blood onto the floor. A graphic traces the spread of the humanity-ravaging virus around the globe via international flight routes.
- Knockout, Puffer, Dolphy, Rachel, Mighty Joe, Daylight, Jenny, Pete, Kevin, Alberto, Blythe Baxter, Zoe Trent, Pepper Clark, Penny Ling, Vinnie Terrio, Sunil Nevla, Minka Mark, and Russell Ferguson guest star in this film.
- The storyline continues in Thomas, Twilight, and the Dawn of the Planet of the Apes.