The Taken King focuses on Oryx whose son Crota was the antagonist of Destiny's first DLC, The Dark Below. In revenge for the Guardians' defeat of Crota, Oryx sent his Taken, hive warriors altered by the Darkness, throughout the solar system and they subsequently converted many Vex, Cabal, Fallen, and other Hive to become Taken as well. This allowed him to acquire an overwhelming army to enact his vengeance. The story begins with the Awoken attempting to attack Oryx's ship, the Dreadnaught, in the rings of Saturn. However, this ends with the Awoken fleet being destroyed and the apparent deaths of Queen Mara Sov and Prince Uldren Sov. With the guidance of Ghost, the Guardian is sent to investigate a Cabal distress signal on Phobos, but is ambushed and forced to evacuate, where it is revealed to the Guardian that Oryx has corrupted the Cabal in order to make his Taken army. In the Last City, the Vanguard discuss the attack and the Awoken, until Eris Morn interrupts and tells the Vanguard of Oryx's intentions. The Guardian is then sent to obtain a new power to combat this new enemy: Titans are sent to Mercury to find a rogue clan of Titans known as the Sunbreakers; Warlocks must perform a Stormcaller ritual within a lightning storm on Mars; Hunters must find Cayde-6's old friend named Tevis, a Nightstalker Hunter, in the Black Garden.

Cayde-6 then sends the Guardian to search his secret stash in the Russian Cosmodrome for a stealth drive to infiltrate Oryx's ship with. He convinces the Tower's shipwright, Amanda Holliday, to attach it to Eris's ship, as it has the scent of the Hive from her many years spent on the Moon. The Guardian uses Eris's modified ship to attempt to infiltrate the Dreadnaught, but is spotted. The Dreadnaught's main weapon is fired, destroying Eris's ship. Narrowly escaping death by teleporting out of the ship and onto the Dreadnaught, the Guardian and Ghost explores and disables the weapon. The Guardian also discovers that the Cabal have also boarded the Dreadnaught and plan to destroy the ship. In order to reach Oryx, the Guardian must steal what remains of Crota's soul from his tomb on the Moon so that they can through a portal on the Dreadnaught called a Rupture. The Guardian is able to get cloaking tech from the Warmind Rasputin to sneak into Crota's tomb, and successfully recovers Crota's soul with help from Eris when the cloaking tech fails. The Guardian infiltrates the Dreadnaught and is able to through the Rupture, and after fighting Oryx's guards, the Guardian reaches Oryx. After defeating him, Oryx draws the Light that was gathered in his sword and vanishes. The mid-credits scene shows Eris Morn touching Oryx's sword and then watches it crumble, taking the crystal that was inside of it.

After returning to the Tower, the Guardian engages further in the Taken War, and is tasked by the Vanguard of the Tower and Petra and Variks of the Vestian Outpost to eliminate remaining Taken threats across the Solar System. Although it was believed that Oryx was destroyed, he in fact survived, thus prompting a team of guardians to reboard the Dreadnaught ("King's Fall" raid) and defeat Oryx's mightiest warriors: a powerful knight called the Warpriest, a fierce ogre named Golgoroth, and the daughters of Oryx, the Deathsingers (powerful Hive wizards), Ir Halak and Ir Anûk, before finally facing and destroying Oryx, The Taken King, who appears in a much more powerful and larger form than the first encounter with him. When Oryx dies, his body turns to stone and falls into Saturn's atmosphere, burning up as it enters the Gas Giant.

Some time following the aftermath of Oryx's defeat, a Taken prince called Malok, Pride of Oryx, arose to try and claim the throne as the new Taken King. Learning of this new threat, Variks tasks the Guardian with hunting down Malok on the Dreadnaught, with the intent of having him imprisoned in the Prison of Elders. Finding Malok and after the ensuing battle, Malok flees, forcing the Guardian to find clues to the prince's new whereabouts. Tracking him down to the Shrine of Oryx on the Moon, Eris tasks the Guardian with destroying Malok, instead of capturing him for Variks, believing it best for him to be eliminated, to which the Guardian does.