Fireteam Osiris is deployed to the Covenant-controlled planet of Kamchatka to extract the rogue Dr. Catherine Elizabeth Halsey, who claims to have information on a series of devastating attacks on several human worlds, during a battle between Covenant forces and the Prometheans. While the team is successful in retrieving Halsey and eliminating the Covenant leader Jul 'Mdama, Halsey informs them that a new threat is about to emerge.

Elsewhere, the Master Chief leads Blue Team on a mission to secure a derelict ONI research station known as Argent Moon. However, while advancing through the station, a Covenant fleet arrives, forcing Blue Team to scuttle the station instead. During the sabotage, the Chief receives a cryptic message from Cortana, directing him to the planet Meridian. John is ordered to return to Infinity upon destroying Argent Moon, but he and Blue Team disobey orders and set out after Cortana, forcing Captain Lasky to list the rogue Spartans as AWOL. This causes consternation aboard the Infinity, as Halsey believes that Cortana's survival through the use of Forerunner technology makes her unpredictable and untrustworthy.

Lasky gives Fireteam Osiris the objective of finding and capturing Blue Team. Osiris is deployed to Meridian in order to pursue Blue Team, where they find a human colony under attack by Promethean forces. During their pursuit, they encounter the Warden Eternal, a Promethean serving as Cortana's enforcer. After temporarily defeating the Warden, Osiris catches up to Blue Team, ordering them to stand down and return to Infinity. Blue Team, instead, board one of the eponymous Guardians: large Forerunner constructs capable of devastating colonies. Osiris themselves barely escape the colony's collapse as the Guardian activates and disappears. The Guardian emerges on the Forerunner planet Genesis, where John and Cortana reunite. Cortana says her rampancy was cured by the same Forerunner technology that saved her.

Osiris is deployed to the Sangheili homeworld of Sanghelios, where they plan to use a dormant Guardian resides there to travel to Blue Team's location. However, the planet is engulfed in civil war; the remaining forces of the Covenant have chosen to make their last stand there. To expedite their mission, Osiris joins forces with the Arbiter and help him strike a crucial blow at the Covenant remnant. The Arbiter secures victory for his forces while Osiris successfully boards a Guardian with the help of Commander Palmer.

On Genesis Osiris encounters the planet's caretaker, the artificial intelligence 031 Exuberant Witness, who allies with them to stop Cortana. Osiris catches up to Blue Team, who reveal Cortana is planning on using the Guardians to achieve galactic peace through forcible disarmament. Master Chief, aware of the massive devastation Cortana's plan will cause, attempts to convince Cortana to stand down. She refuses and confines Blue Team in a Forerunner prison, to prevent them from interfering with her plan. Osiris manages to transfer control of Genesis back to Exuberant, who wrests the prison from Cortana as she leaves the planet via a Guardian.

Artificial intelligences across the galaxy begin swearing allegiance to Cortana and her plans. Cortana locates Infinity and prepares to disable it, but Lasky has the ship's AI Roland, who is still loyal to Infinity, engage slipspace away from Earth and commit to random jumps until they can develop a way to combat Cortana. With Blue Team recovered, Osiris returns to Sanghelios to reunite the SPARTAN-IIs with an injured Commander Palmer, The Arbiter, and Dr. Halsey.