The Flood takes place between September 19, 2552 and September 23, 2552. It is based on the game Combat Evolved. It begins as the UNSC cruiser UNSC Pillar of Autumn is exiting slipspace (randomized vector due to the Cole Protocol) after retreating from the fallen military base at Reach. Cortana's exit vector led the ship to a system found when she had decrypted Forerunner glyphs found by John-117 on Sigma Octanus IV. When the Pillar of Autumn drops out of slipspace, she encounters a massive ring-world in orbit around Threshold, a gas giant. This world is called Installation 04, also known as Alpha Halo.
In the system there is a host of Covenant Ships, who notice the lone ship. A Prophet forbids the fleet to fire on the Pillar of Autumn, for fear of damaging the ring. Instead, the Covenant are willing to sacrifice more lives in order to board and capture the ship rather than blasting the ship to pieces. As a result of this, the Pillar of Autumn and her crew are able to destroy four Covenant ships, but not without being further crippled from the Covenant onslaught. Meanwhile, technicians on the Autumn are preparing for battle and thawing out a single soldier from cryogenic sleep, presumably the last SPARTAN-II known as John-117.
The Covenant proceed to take out the Autumn's defenses and board the ship. Deprived of defensive options, the Autumn's captain, Jacob Keyes, initiates the Cole Protocol and tells the crew to abandon the ship. John-117 is entrusted with the AI Cortana; given the wealth of tactical information the AI contains, (force deployment, weapons research, and the location of Earth) Keyes cannot allow Cortana to fall into Covenant hands. John fights through the Covenant invaders, reaches the last remaining lifeboat, and heads to the surface of the ringworld known as Halo. At the same time, a special contingent of Orbital Drop Shock Troopers, or ODSTs, leave the Autumn via Human Entry Vehicles. On the ground, the ODST Commander, Major Antonio Silva and his second-in-command, Melissa McKay, prepare to establish a ground base from where the human forces will launch their guerrilla resistance against the Covenant. Silva is aided by a Class C Military AI named Wellsley, after the Duke of Wellington, who advises them to capture a high butte.
Meanwhile, a Covenant Grunt named Yayap leads his squad into the Pillar of Autumn. Extremely cautious and cowardly by nature, Yayap and his team decide to rescue a Covenant Special Operations Elite wounded by John-117, rather than fight the humans. The five small aliens drag the black-armored Elite back to their craft and escape the deteriorating Autumn as it plunges towards the Ringworld's atmosphere.
An Ossoona by the name of Isna 'Nosolee manages to survive using active camouflage to board Keyes' lifeboat after tracking him down in an attempt to take him hostage. However, the Captain sees him and shoots him with a Corporal's M6D pistol. Isna's corpse later allows the Covenant to realize that they should capture Keyes. Keyes and his crew are forced to evade Covenant forces after they crash onto Halo. Finally, they are betrayed by Ensign Ellen Dowski. Consequently everyone, including the Ensign, is executed, save the Captain, who is captured for interrogation aboard the Truth and Reconciliation.
John-117 lands on Halo and helps rescue Marines from their lifeboats, while the ODSTs secure Alpha Base after a clash with Covenant forces. Yayap is rewarded for his rescue of the Elite, Zuka 'Zamamee, with a terribly dangerous assignment as the Elite's assistant.
John-117 and a squad of Marines board the Truth and Reconciliation, rescuing the Captain. Keyes has learned that the ringworld they are on has vast significance to the Covenant (they believe that "Halo", as they call the ring, is a weapon of unimaginable power). Escaping from the Covenant cruiser, Keyes gives John-117 the mission of finding the Control Room of Halo before the Covenant does. Meanwhile, Zuka ’Zamamee and Yayap are given permission to hunt for John-117, but fail in their attempts. Meanwhile, Lieutenant McKay and her company assault the now Covenant-controlled UNSC Pillar of Autumn for supplies and vehicles.
Keyes, along with a squad of Marines and Sergeant Johnson, are dropped into a swamp in an effort to discover a weapons cache. The Marines took prisoner a disillusioned Elite named 'Qualomee, who claimed to be delivering a shipment of weapons to a force guarding the structure. Pushing deep into a mysterious structure, the squad finds something unlike anything they have seen before - dead Covenant freakishly ripped open and scattered about. In a locked room, the squad discovers the cause of the fatalities - the Flood. These bulbous aliens attempt to latch themselves onto the Marines, and despite being fragile, the sheer number of the creatures overwhelm all the soldiers, tapping into their nervous systems and taking over their bodies. One soldier, Private Wallace A. Jenkins, is left still semi-conscious and painfully aware of his predicament. He has a limited ability to control his movement or actions, because the infection form was weakened from the hibernation.
John-117 and Cortana discover the location of the Control Room. John then inserts Cortana into Halo's computer network. However, Cortana realizes that the ring isn't a weapon as they understood at all. However, before John can press her with questions, Cortana tells John-117 to find the Captain, unaware that they are too late. John-117 is dropped alone into the swamp where Keyes disappeared. Heading into the same structure, John-117 follows the subterranean passages down to the same room where Keyes and his men were attacked. He discovers their horrible fate through a recording from PFC Wallace A. Jenkins' helmet cam, and fights his way to the surface. There, he meets up with Marines and heads to a tower for evac. Suddenly, John is teleported away from the swamp by Halo's resident AI, 343 Guilty Spark. John-117 is informed that the creatures he has encountered are called the Flood, a virulent parasite that infects its enemies to produce more of itself. Guilty Spark wishes to activate Halo's defenses to wipe out the Flood, but needs John-117's help in recovering the "Index" to the installation, which allows the activation of the ring. Fighting more and more Flood, John recovers the Index and is teleported back to Halo's control room.
Meanwhile, the UNSC forces of Alpha Base are forced to defend themselves from a surprise attack by Covenant forces who were attempting to kill John-117, unaware that he was absent. After the failed attack, UNSC forces attempted to ambush a Covenant recovery team, but were interrupted by a Flood attack. Jenkins attempted to commit suicide by throwing himself into the line of fire, but was instead captured.
Back in the Control Room, Guilty Spark gives John-117 the Index to activate Halo, but is stopped by the furious Cortana. Cortana explains that Halo is a weapon, but it doesn't kill the Flood - it kills their food, meaning humans, Covenant, and any other sentient life in the galaxy. Realizing that they have to stop Guilty Spark from activating Halo, Cortana and John-117 decide to destroy Halo by detonating the crash-landed Pillar of Autumn's fusion reactors. In order to do this, they need Captain Keyes' neural implants to activate the countdown. In order to slow Guilty Spark's progress, the pair overload three generators that amplify Halo's weapon. In order to fire Halo, they would have to be repaired. Cortana discovers the Captain is still alive, held prisoner once again aboard the Truth and Reconciliation, now in the hands of the Flood who are trying to escape Halo with the ship. John fights Covenant and Flood to the Captain, but finds out he is too late; the Captain, after successfully resisting an interrogation by the Flood, was being transformed into a proto-Gravemind. John retrieves the implants and leaves the Truth and Reconciliation for the Pillar Of Autumn.
While John and Cortana head to the Autumn, Alpha Base is evacuated. Silva decides to retake the Truth and Reconciliation and pilot the ship away in order to avoid being on Halo when the Autumn blows. The ship is taken successfully, but McKay realizes that Silva is blinded by the thought of promotion and glory to the danger of the Flood; ignoring Wellsley's objections, he fails to realize that if even one Flood specimen escaped containment on Earth, the entire planet could fall. An engineer notifies McKay of a vital power line (should it be severed, the unregulated energy would destroy the ship). Jenkins, who is infected but still coherent, attempts to destroy the line, but falls short. Realizing that the destruction of the Flood is far more important then Silva's promotion, McKay cuts the cable by activating a frag grenade, sending the Truth and Reconciliation crashing into Halo, nose first, killing everything aboard.
At the wrecked Autumn John-117 is forced to destabilize the fusion reactors manually as 343 Guilty Spark and his robotic Sentinels try to stop them. On the way to the Engine Room, John-117 is nearly infected by the Flood, but Cortana saves him. Once the countdown until detonation has begun, Cortana radios for dropship evacuation, but the transport is shot down by Covenant aircraft. A disgruntled Zuka 'Zamamee attempts to ambush John, but is killed by a hail of grenades. Cortana directs John to a Longsword Interceptor still docked in the Pillar of Autumn hangar. Gunning the engines, John and Cortana escape the ring just as the Autumn explodes, ending the threat of the Flood. Cortana scans for survivors and realizes that they are seemingly the only two who have survived. Cortana tells John-117 that the fight is finished, to which John replies, "No, the Covenant is still out there, and Earth is at risk. We're just getting started."