One year after the SIVA Crisis, Cabal forces of the Red Legion launch an aerial assault on the Last City, destroying the main portion of the Tower, the headquarters of the Guardians. The player's Guardian and their Ghost respond by assisting the Vanguard in assaulting the Red Legion command ship. As they confront the Red Legion's commander, Dominus Ghaul, his forces attach a device to the Traveler and begin draining it of the Light, the power used by the Guardians. The Guardian loses their powers and is nearly killed by Ghaul. Waking two days after the attack, the Guardian locates their Ghost. They find a haven known as "the Farm" in the European Dead Zone (EDZ) with the assistance of Suraya Hawthorne, a non-Guardian human from the outskirts of the Last City.
The Guardian follows a vision to encounter a shard of the Traveler hidden in a forest within the EDZ. Ghost interfaces with the shard and both its and the Guardian's Light are restored. After restoring long range communications, Hawthorne intercepts a distress call from Commander Zavala, urging surviving Guardians to travel to Saturn's moon Titan and assist in mounting a counter-offensive. Against Hawthorne's objections, the Guardian travels to Titan, which has been overrun by the Hive. With assistance from Deputy Commander Sloane, they learn that the Red Legion was dispatched to the Milky Way in response to a distress call sent during the Taken War two years prior, and that Ghaul possesses a superweapon known as the Almighty, a space station capable of destroying stars. Resistance to Cabal rule has resulted in entire star systems being destroyed. The intelligence also reveals that the Almighty is positioned near the Sun, breaking up the planet Mercury as fuel. Zavala tasks the Guardian to find Ikora Rey and Cayde-6 to assist in a counterattack to retake the Last City. During this time, it is shown that Ghaul, aided by his mentor, the Consul, overthrew Emperor Calus and took control of the Cabal, and has been studying the Traveler in order to learn how to use the Light and legitimize himself as Emperor.
The Guardian locates Cayde-6 on the centaur planet Nessus, which has almost been completely transformed by the Vex. With the aid of Failsafe, an AI from the crashed starship Exodus Black, the Guardian frees Cayde from a Vex portal loop, and claims a teleporter for use in taking back the City. Cayde directs the Guardian to find Ikora on the Jovian moon of Io, where she had gone to find answers about the Traveler. Ikora and Io researcher Asher Mir directs the Guardian to locate a Warmind, an ancient defensive AI for intelligence on the Almighty. Afterwards, the Vanguard reunites at the Farm and conclude that the only way to retake the Last City and save the Traveler is to shut down the Almighty first, eliminating the possibility of it destroying the Sun. The Guardian boards the Almighty and destroys the weapon, signaling Zavala to begin the counterattack. As the Vanguard begins the assault, the Consul admonishes Ghaul for his obsession with the Traveler, and urges him to take the Light; Ghaul is reluctant until the Consul kills the Speaker, whom Ghaul had captured and tortured to try and learn more about the Traveler. Ghaul then proclaims that he will take the Light, and strangles the Consul in a fit of rage.
The Guardian returns to Earth to assist in the counterattack and infiltrates Ghaul's command ship alone to save the Traveler. Ghaul forcibly takes the Light, corrupting it, and uses its power against the Guardian, but the Guardian is successful in defeating Ghaul. Ghaul reemerges as a massive ethereal figure who then speaks to the Traveler directly. In doing so, the Traveler wakes from its long sleep, destroying the device that was harvesting its power and killing Ghaul. It sends a massive shockwave, restoring the Light and decimating the Red Legion's forces. The game ends with a posthumous voiceover from the Speaker, reminding all that the Light can never be stopped. The Guardian and Ghost convene with Zavala, Ikora, Cayde, and Hawthorne at an undamaged portion of the Tower, with the Vanguard returning to their old duties and Hawthorne assuming a new post there. In a post-credits scene, the shockwave sent by the Traveler is shown reaching the entire system. The wave of Light extends beyond the Solar System and spreads beyond the Milky Way, before panning across a fleet of dark, unknown ships sitting some distance away in extragalactic space.
Following Ghaul's defeat, a massive Cabal ship called the Leviathan appears in orbit of Nessus, under the control of the exiled Emperor Calus. Calus invites Guardians to complete a series of challenges before reaching his throne ("Leviathan" raid). A fireteam of Guardians complete his challenges before facing Calus himself; however, after overcoming his strange powers and defeating him, they discover that they were fighting a mechanical doppelganger. The real Calus speaks through the machine, claiming that what they know is a lie and that there is a truth beyond what the Speaker had told them.