The game begins at around 4:00pm, October 20th, 2552. The majority of an ODST squad are preparing for the mission on board the UNSC Say My Name orbiting high above New Mombasa, Kenya. They are grouped around a holo-table, which shows the Covenant Prophet of Regret's CAS-class assault carrier hovering near the city's Orbital Elevator. Corporal Taylor "Dutch" Miles, Lance Corporal Kojo "Romeo" Agu, and Private First Class Michael "Mickey" Crespo are gathered around the holo-table. The Lance Corporal "Rookie" is asleep in the back of the room.
Romeo jokingly remarks how the UNSC Navy managed to put up a fight during the Invasion of Earth, but still allowed a Covenant carrier to slip by the Orbital Defense Platforms surrounding the planet. Dutch criticizes Romeo, stating that the navy left the lone ship for the Marines to infiltrate. The ODSTs are soon put on alert when their team leader, Gunnery Sergeant Edward Buck, enters the room with an attractive ONI operative named Veronica Dare. Romeo utters "Hello, beautiful" in response to Dare's appearance, catching Buck's attention and prompting him to order the ODSTs to their SOEIV "drop pods".
While walking to the nearby armory, Buck is stopped by Dare, who remarks that the members of his squad are replacements. Buck acknowledges the problem, but notes that after 27 years of war with the Covenant, very few veterans are left in the UNSC. Conflicted about what she likely told him prior to entering the room, Buck confronts Dare about the objective of his team, stating the Assault Carrier (carrying the Prophet of Regret) is a more vital concern than her covert mission. Dare reminds him that they have orders to follow, and that she should be referred to as "Captain", in keeping with military regulations.
Buck directs the Captain to her pod, where Romeo asks about her; obviously angry about the mission, Buck confronts the curious Lance Corporal, replying that she is their "new boss". He gives a short speech to his men to motivate them for the drop, and hands a SRS99D Sniper Rifle to Romeo, drawing questions from the squad, who were anticipating a close range battle inside the Covenant Assault Carrier. While en route to his own drop pod, Romeo rudely awakens the Rookie, hitting him with the butt of his rifle (at which point the camera changes to a first-person view) while the Rookie lies asleep in his pod. Dutch pushes Romeo out of the way and hands the Rookie a silenced SMG, telling the ODST to relax despite Romeo's obnoxious behavior; the Rookie's pod is then closed, spun around, and lowered into the launch bay to begin drop preparations.
Marine forces are informed by Dare that the Covenant Army is massing beneath the Assault Carrier for an organized retreat. Dozens of ODSTs are launched into Earth's atmosphere in a coordinated drop to infiltrate and capture the Prophet of Regret aboard the Assault Carrier. They pass by a few destroyed Frigates in orbit around the elevator, and begin to enter cloud cover above the city. The Captain then orders the squad to adjust their trajectory and drop locations; sending the ODST's way off of their intended course.
Before the ODST's are able to deploy their internal parachutes, however, Dutch picks up a radiation alert in his pod, and the Assault Carrier proceeds to enter Slipspace, closely followed by the Stalwart-class light frigate UNSC In Amber Clad. An EMP emitted by the Slipspace rupture disables the drop pods before they are able to deploy their parachutes; the ODSTs are scattered across New Mombasa. Dare's commandeered squad, farthest away from the Slipspace rupture, manages to survive the fall, but the remaining ODST's aiming for the Carrier are killed in action. During the fall, the Rookie's pod collides with Mickey's pod, sending it out of control. The impact knocks the Rookie unconscious.
Six hours after the drop (10:02pm), the Rookie awakens to the sound of two Phantoms flying nearby. He soon regains his situational awareness, discovering that his drop pod is lodged in a building at least twenty feet off the ground. With no choice, he jumps out of the pod, and falls to the street, slightly injuring himself when he hits the ground. After combing the area for medical supplies, he heads in to the city to find his squad.
Almost immediately after starting out, the Rookie encounters a few Covenant patrols covering a small area. The Rookie uses his silenced weaponry to eliminate the patrols, after which he is alerted to a ringing data terminal. Upon accessing the terminal, the Rookie is connected to the Superintendent, a second-generation "dumb" AI tasked with maintaining the city's infrastructure. The A.I. provides the Rookie with data that had been previously unlocked by Dare. The Superintendent begins to assist the Rookie, giving him maps, marking notable locations throughout the city, and providing warnings using road signs.
As the Rookie travels throughout the city, he finds clues regarding the fate of his squadmates. When the Rookie finds a clue, the game's perspective shifts to that of the relevant ODST.
Six hours earlier, Buck had landed somewhat safely (if uncomfortably) and made radio contact with Dare, who told him that she had been trapped in her drop pod. With the assistance of Marines in the area, Buck fought his way to her position. Along the way, he noticed a "family feud" within the Covenant, as many Sangheili were found dead and seemed to have been killed by the Brutes. By the time Buck got to Dare's pod, she was nowhere to be found. Buck noticed a Huragok, and saw that it was holding Dare's helmet in one of its tentacles. Curious, the alien began to examine Buck. Having mistaken its curiosity for hostility, Romeo sniped the inquisitive alien, inadvertently triggering the bomb mounted on its back. The resulting explosion threw the helmet out of sight, although the Superintendent recorded a video showing where it landed. Romeo and Buck regrouped, the former stating his belief that Dare was dead. The Rookie later finds the helmet.
Meanwhile, Dutch landed in the Uplift Wildlife Reserve, where he led a Warthog charge in an effort to breach Covenant defenses and secure the long-departed carrier's landing zone. Mickey had landed nearby, and stumbled upon retreating Marines from the 405th. Mickey used a Scorpion to bring the Marines to their rally point: the entrance to ONI Alpha Site. There, he and Dutch regrouped and found a desperate police officer, who was searching for an explosives expert. Mickey, who had originally hoped to dig in at the rally point and wait for backup, was pressed into service, and he and Dutch headed to the ONI Alpha Site with the police officer in tow.
The two ODSTs worked with the officer and several Marines to defend the ONI complex. Dutch and Mickey used explosives to destroy the bridge leading to the base, but the Covenant easily countered by using Phantoms to land troops past the broken bridge. The courtyard was quickly overrun by Covenant forces, prompting the besieged humans to retreat to the structure's interior. The humans are eventually forced to retreat from the building using a police Pelican. As they fled, they destroyed the base using remotely-detonated explosives, preventing the Covenant from using the structure and it's contained information. While in flight, Dutch and Mickey managed to re-establish communication with Buck; they headed to the NMPD Headquarters to pick him up.
Upon arriving and attempting to land on a rooftop to pick up Buck and Romeo, Mickey, Dutch and their NMPD allies are attacked by Banshees, and their Pelican is shot down. Buck and Romeo fight their way across the rooftops of the NMPD HQ to the downed Pelican and their squadmates. There, the four ODSTs used missile pods, heavy machine guns, and rocket launchers to defend the building from Banshees and Phantoms with landing parties. They were successful in repelling the Covenant assault, but in the process, Romeo was badly wounded by a Brute Chieftain, and their Pelican was damaged and left inoperable.
Buck led the group to Kikowani Station, planning to use the tram system to escape the city, stabilizing Romeo with biofoam along the way. Upon arrival, however, the group discovered that the tram tunnels had been flooded. They proceeded to hijack a Phantom and escape the city, fighting their way past enemy Banshees and even a Scarab in the process. Along the way, they noticed several CCS-class battlecruisers moving toward the crater left by the Assault Carrier's Slipspace jump. After escaping the city proper, Buck realized where Dare was, and ordered Mickey to turn back and set him down.
Meanwhile, the Rookie, having made his way to the Superintendent's Data Center, finds Captain Dare locked in on sub-level nine. She reveals that her orders were to fight her way to the A.I.'s data center and retrieve the information that had recently been discovered about what lay beneath the city, and deny access to the Covenant. The data center, however, had been infested with an entire hive of Drones, which in turn were supported by numerous other Covenant forces. She explains that this was why she requisitioned a whole squad for her mission: it would have been suicide to fight these forces alone.
Dare and the Rookie fight their way to the data center, arriving just as the severely damaged Superintendent finally shuts down. Closer inspection of the AI's core by the pair reveals a lone, hiding Huragok. Dare reveals an ONI discovery: the Huragoks were enslaved by the Covenant, and have little love for their overlords. She also reveals that this particular Huragok, named Vergil (due to its absorption of the Vergil subroutine in the Superintendent), has combined it's knowledge with the information possessed by the Superintendent, information that can aid humanity in the war.
The two convinced the Huragok to follow them just as the Covenant arrived; Buck arrives at the same time. They escape the data core and fight though hordes of Covenant troops before reaching an elevator, which takes them to the city's coastal highway. Buck informs Dare and the Rookie that he has his stolen Phantom waiting in the shipyards down the highway. Vergil powers up an Elephant; Dare drives, while the Rookie and Buck provide supporting fire from a Warthog, and later, a Scorpion.
More Covenant ships enter the city, and the fleet begins to glass the area in an attempt to uncover the buried Forerunner Portal to the Ark. Buck, having witnessed glassing during the Fall of Reach, is particularly disturbed by the sight. A Scarab manages to score a direct hit on the Elephant, damaging it severely and forcing the ODSTs to abandon their vehicles and take cover inside the building entrance to Uplift Wildlife Reserve. Buck orders Mickey to provide extraction instead of waiting for them to arrive.
The ODSTs endure multiple Covenant attacks while waiting for Mickey to arrive. When Mickey and the rest of the squad reach their position, the group boards their captured Phantom, narrowly avoiding a Covenant Carrier's glassing beam.
A month later, Admiral Terrence Hood gives Sergeant Major Avery Johnson clearance to interrogate Vergil on an ONI orbital facility. Dare warns Johnson to be careful. As the two enter the room, they see Vergil toying with the optics for a drone fighter. The squad is clustered around the Huragok, with the Rookie asleep in a corner. Johnson casually tosses his lighter to the delicate (and flammable) creature, much to Dare's alarm, which Johnson ignores. Johnson expresses the mutual loathing that humans and Huragok share towards the Brutes, and appeals to Vergil to help the human cause, stating that "You're (Vergil) gonna tell me exactly what they're looking for. And then, you're gonna help me stop 'em." Vergil raised the lighter, flicked it open, and lit the cigar that Johnson just placed in his mouth, suggesting that this Engineer is friendly and willing to cooperate with the humans.
An additional scene plays upon completing the game on Legendary. The Prophet of Truth is seen in the chamber that houses the Superintendent's core, smiling as more Huragok uncover an extensive Forerunner complex beneath the dirt. There is no clear indication as to whether this structure is part of the previously uncovered portal generator or something else entirely.