In the year 2029, John Connor, leader of the human Resistance, leads the war against the machines. At the final Los Angeles offensive, he is notified by his army unit that Skynet will attack on two fronts — past and future, thereby changing warfare forever. Connor sets up two units, one to strike at Skynet's main defense grid, and a second (led by Kyle Reese and himself) to destroy Skynet's main weapon, a time machine hidden at a remote storage facility.

Before the Resistance can reach the machine, Skynet sends back a T-800 to the year 1984 to kill John's mother, Sarah Connor. Learning of this, Connor sends Kyle Reese back in time to protect her. As Kyle floats in the machine's magnetic field, he experiences memories of his 12-year-old self with young Sarah, and a warning that "Genisys is Skynet" and will come online in 2017. Moments before Kyle disappears, he witnesses one of the Resistance fighters, Alex, attacking John.

The T-800 arrives in 1984 Los Angeles, but is quickly dispatched by Sarah and "The Guardian", a reprogrammed T-800 (Model 101) with aged human tissue. Shortly after, Kyle is ambushed by a T-1000 and unexpectedly rescued by Sarah and the Guardian. Kyle finds out that the original timeline has been altered: Sarah already knows about Skynet, Judgment Day, and Reese's role as both her protector and John Connor's father (although Kyle does not yet know he will become father to John). After the T-1000 tracks the trio, they manage to lure it to a sewer where Sarah disintegrates it with acid.

Sarah then explains to Kyle that the Guardian was sent to protect her from the T-1000 back in 1973. Both Terminators' arrival caused a fractured timeline that, therefore, differs from Kyle's. After saving Sarah, the Guardian began training her to face her destiny. The Guardian has built a time machine similar to Skynet's and Sarah plans to make use of a "one and only chance" to jump with Kyle to 1997 to prevent Judgment Day. However, Kyle, convinced of his new memories, persuades Sarah and the Guardian that they should travel to 2017 instead. Both Kyle and Sarah time-travel while their Guardian spends the next 33 years preparing for their arrival.

In 2017, Kyle and Sarah materialize in the middle of a busy highway and are apprehended by police. The Guardian watches from a distance and follows them to a hospital. While being treated for injuries, Sarah learns about "Genisys", a soon-to-be-unveiled operating system that will be used on every computer, mobile device, and military application on the planet. She and Kyle are then unexpectedly rescued by her son, John Connor (an adult version of himself). As he leads the pair to a parking garage, the Guardian appears and shoots John, who revives himself, revealing himself to be a nanomachine hybrid. John explains that shortly after Kyle was sent back, he was infected by Alex, a prototype T-5000, and was subsequently transformed. John, now the T-3000, tries to convince Sarah and Kyle to join the machines and end the conflict, but they refuse. After a brief battle, the T-3000 is temporarily incapacitated with an MRI machine.

The Guardian takes Kyle and Sarah to a safe house near the Golden Gate Bridge, where they make final preparations to destroy the Genisys mainframe before it comes online. The T-3000 pursues them to the Golden Gate bridge, where Kyle, Sarah, and the Guardian are all taken into police custody. While awaiting interrogation, the trio is freed by Detective O'Brien, who was saved by Kyle in 1984 and is convinced that they are time-travelers with good intentions. The three hijack a helicopter on the rooftop and head toward the Genisys building, with the T-3000 in close pursuit. During the airborne chase, the Guardian dive bombs into the T-3000's helicopter, causing it to crash.

Emerging from the helicopter crash, the T-3000 enters the Genisys building, kills the security guards, and advances the countdown clock from 13 hours to 15 minutes. As Genisys begins to gain sentience, the Guardian, Kyle and Sarah plant bombs at key points in the facility while holding off the T-3000. After a lengthy battle, the Guardian traps the T-3000 in the magnetic field of the prototype time machine and destroys it, but not before the T-3000 manages to throw the Guardian into the T-1000-like liquid just beneath the magnetic field. Both Kyle and Sarah manage to reach a bunker beneath the facility moments before the time machine explodes, setting off the bombs, and preventing Genisys from coming online. The Guardian appears, now upgraded with T-1000 components, and helps them find a way out of the debris.

Their mission completed, the Guardian, Kyle and Sarah travel to young Kyle's home, where they repeat the warning about Genisys to young Kyle. Sarah is relieved to know that she is now free to choose what to do with her future. She decides to stay with Kyle. Unknown to them, the Genisys system core was located in a hidden subterranean chamber and has survived the explosion and can be seen as a holographic projection of the now self-aware Skynet.