The game begins in the 28th Century where a Ghost is searching among the detritus of Old Russia until it finds and resurrects the player's Guardian, who had been killed in an ancient battle—upon resurrection, Guardians have no memories of their past. Ghost then guides the Guardian to a jump ship and they take it to the Tower. There, they meet the Speaker, who briefs them about the Darkness. The Guardian is then tasked to probe the nearby Cosmodrome, where humanity used to launch its forays into outer space, fending off Fallen enemies and eventually the Hive, who were thought to have been confined to the Moon.

The Guardian discovers that an old Russian Warmind called Rasputin, an AI built to defend Earth, is still alive and acting with unknown intent. The Guardian also tracks down codes to raise an ancient Array to connect it to long-lost colonies throughout the Solar System, that Rasputin uses to spread its influence to other parts of the system. They then set off to the Moon in search of a lost Guardian who was looking for a way into the Hive fortress. After locating his corpse and dead Ghost, the player's Guardian's Ghost discovers that the Hive are raising an army and plan to invade Earth.

The Guardian quickly sets about disrupting their efforts, including shutting down a ritual that the Hive were using to drain power from the Traveler using a piece of the Traveler (which the guardian frees, allowing it to return to the Traveler), and destroying a powerful weapon called the Sword of Crota, and severing their long-distance communications. Around this time, the Guardian is contacted by the Exo Stranger, a mysterious woman who summons them to Venus to face a new enemy, the Vex.

When the Guardian arrives on Venus, the Exo Stranger describes the Vex as an evil so dark it despises other evil. She tells them about the Black Garden, a city where the Vex are born, and implores the Guardian to find it and rip out its heart, as it is the only way the Traveler will begin to heal. Ghost says that they need to speak to the Awoken, who lurk out in the Reef (the asteroid belt) and refuse to take sides in the galaxy's wars. The Exo Stranger then leaves, as she did not have time to explain things further.

Once the Guardian arrives at the Reef, they meet the Queen of the Reef, Mara Sov, and her brother, Prince Uldren Sov, who tells the Guardian that they will help them locate the Black Garden if they bring them the head of a Vex Gate Lord. The Guardian travels back to Venus, where they uncover the Archive, which reveals secrets about the Vex, including the location of a place called the Vault of Glass, and pathways across the galaxy. After defeating Draksis, a Fallen Kell of the House of Winter, the Guardian confronts the Vex Gate Lord, claims its head, and returns to the Queen, who tells them to take its eye to the Meridian Bay on Mars, where it can be used to enter the Black Garden.

After arriving on Mars in the Meridian Bay, Ghost informs the Guardian of its inhabitants. The Cabal have been trying to break the encryption on the Vex Gate with only limited success, but they do control many of the places that the Guardian needs to visit on Mars thanks to their Exclusion Zone, which nobody had ever penetrated. The player's Guardian becomes the first to penetrate the Exclusion Zone and heads to the Garden's Spire, which charges the Gate Lord's eye.

They also travel to the Buried City, the birthplace of many technological wonders where they discover an AI that used to be linked to the Warmind of Mars, but, after the activation of the Array, is now controlled by Rasputin. With the Vex now present on Mars, the Guardian finds out what they are doing; they are returning to their home, the Black Garden.

The Guardian then sets off to the Black Garden. After going through a teleporter, they find themselves in a place that is not on any map of known space and time. After several battles, the Guardian reaches the heart of the Black Garden, which the Vex appear to be worshipping. The heart summons three Sol Progeny— a group of Vex units called Eschaton Mind, Imminent Mind, and Primeval Mind. After defeating the three Sol Progeny, the heart is destroyed, returning the Guardian and the Garden itself to Mars and lifting the shroud of Darkness from the Traveler back on Earth, allowing it to begin healing.

At the Tower, the Speaker addresses gathered Guardians in a celebratory speech. Over in the nearby hangar, though, the player's Guardian converses with the Exo Stranger, who says that the fight is far from over.

The heart of the Black Garden may have been destroyed, but on Venus, the Vault of glass suddenly reopens. A team of Guardians decide to investigate the mysterious Vault of Glass ("Vault of Glass" raid), described as the "Vex underworld" by the Ishtar Collective. The Vault is a realm where the Vex can control reality, and even erase people from existence. This power is used by the most powerful denizens within the vault: a Vex sub-race called the Gorgons, a powerful Vex mind called the Templar, and Atheon, Time's Conflux.

Both Atheon and the Templar utilize machines called Oracles to do so. While these powers do not extend to outside the Vault, its enigmatic nature has lured countless Guardians to their doom— the most infamous being the ill-fated fireteam of Kabr, the Legionless, which consisted of himself, Future War Cult Warlock Praedyth, and well-known hunter Pahanin. Pahanin was the only member to make it out alive; Praedyth was forever lost in the dark corners of time, and Kabr drank the radiolaria of the Oracles, and was turned into a Vex.

However, in Kabr's last moments, he used his Light to close the Vault and leave behind an artifact, the Aegis, to help any other Guardians daring enough to follow in his footsteps. The new fireteam of Guardians make their descent, and attempt to succeed where Kabr and his fireteam failed. Using the Aegis, the Guardians manage to defeat the Templar and its Oracles. They then successfully traverse the Gorgon's labyrinth undetected before finally reaching Atheon, Time's Conflux.

A central figure of the Vex Conflux network, Atheon is able to send Guardians into the distant past or future at will, and summons versions of Vex from the past and future to aid him. The Vex mind is also capable of summoning Oracles like the Templar, and attempts to erase the new Fireteam from existence. However, despite the astronomical odds, the Guardians fight their way through time, destroy the Oracles, and defeat Atheon, eliminating a major Vex threat.