The Enterprise crew have made little headway since they began their mission to prevent the destruction of all humanity, but word of a Xindi worker on a distant mining colony and the subsequent investigation into the Xindi race bring Archer and Trip into a dangerous trap.
The functionality of the Enterprise is severely impaired by anomalies, but while making repairs, the ship is looted by a group known as the Osaarians. After going after their stolen items, Archer learns that the Osaarians have had contact with the Xindi and frantically tries to question an Osaarian prisoner for information.
Continuing to track the path of the Xindi, the Enterprise travels to a planet, on which Archer, Hoshi, and Reed contract an unusual virus, one which doesn't affect T'Pol. As Phlox desperately tries to find a cure, an alien race with knowledge of the virus' history arrives and plans to curtail any possible further outbreaks.
When the Enterprise docks on a planet in search of a chemical formula, Archer rescues a slave named Rajiin and plans to return her to her home. Rajiin, however, begins exerting a mind control over the crew with the intent to provide information for the Xindi.
When Archer, Reed, Hawkins, and T'Pol attempt to save a Vulcan ship that has called for help from within an asteroid field, they soon find themselves trying to fight off the ship's crew which seemingly has become deranged and aggressive.
A telepathic alien offers Hoshi his services to find out information on the Xindi and its weaponry in exchange for her presence. She soon learns that he refuses to let her return to the Enterprise, which is on its way to a newly discovered sphere.
After setting down on a Xindi colony, Archer, Reed, and Major Hayes infiltrate a facility which produces a substance necessary to create a powerful Xindi weapon and attempt to find the facility head to see what is known about the attack on Earth. Meanwhile, Phlox and Trip take a look at the mechanics of a Xindi-Reptilian instrument of destruction.
After a parasite causes Archer to lose his short-term memory, he wakes up and finds that he's twelve years into the future and was relieved of his command, after which point Earth was ultimately destroyed when the Enterprise crew failed its mission. Dr Phlox figures out how to eliminate the parasite and regain Archer's lost years, but he has to work fast, as the Xindi are returning to pick off whatever humans are still left.
Archer gets caught up in a conflict when he, T'Pol, and Trip end up on a planet which resembles Earth's cowboy wild west. A showdown is coming as the humans are in charge, dispensing prejudice to a race known as the Skargarans who several hundred years ago were in charge and brought the humans over as slave labor.
While trying to make some modifications to the ship, Trip is seriously hurt in the process and the ship gets stranded in an erouspolaric field. Phlox creates a symbiot of Trip to utilize natural tissue for transplant purposes, but the moral dilemma arises when the simbiot, who has figured out how the ship can escape the field, is slated to lose its life to save Trip's.
Archer learns that three Xindi-Reptilians have arrived in Detroit in the year 2004 and he and T'Pol head there to determine their purpose. They learn that the Xindi have employed a man named Loomis to lure unsuspecting humans and force them into service in the ongoing creation of the Xindi superweapon.
When the Enterprise rescues a group of Triannons, it turns out to be a rouse to kidnap the crew and take the Enterprise to their homeworld for the purpose of destroying all who disagree with their ideas. One crew member must also die to atone for the Enterprise's past exploration of a territory the Trainnons find sacred.
The Enterprise makes a risky trek to a test area for the Xindi superweapon's prototype, sustaining ship damage and risking the crew's lives in order to get close enough to snatch the weapon. When an Andorian ship, captained by Shran, comes to the aid of the Enterprise, Shran's objectives for the weapon soon become oppositional to those of both Archer and the Andorians.
The Enterprise crew constructs an elaborate, carefully-executed rouse to elicit from captured Xindi Degra the location where the Xindi superweapon is being designed.
The Enterprise picks up a new discovery, an alien pod, and Phlox treats the seemingly sick alien housed within the pod while Archer determines the alien's intentions. Meanwhile, Reed and Major Hayes come to blows with one another during a Starfleet training session, while T'Pol feels some discomfort at the interactions between Trip and Corporal Amanda Cole.
When the Enterprise tries to travel through a deadly area of the Expanse, Dr Phlox gets the go ahead by Archer to put everyone into temporary comas so that no one is impacted during the transit. The attempt proves more perilous than originally thought, and not only does Phlox find himself needed to guide them out of the rapidly-growing area, he also finds himself hampered by hallucinations brought on by the trip.
Archer and the crew disagree on how to handle the discovery of a group of Xindi-Insectoid eggs. Archer wants to keep them alive, whereas the hesitant crew isn't so sure that's the right move.
As the Enterprise reaches Azati prime and hopes to finally rid itself of the Xindi superweapon, Daniels shows up and takes Archer 400 years into the future, where he discovers a conspiracy that would dangerously set humans against the Xindi.
As the Enterprise recovers from an intense battle with the Xindi, Archer is sent back to the ship, but must deal with the reality of its damage. When the Enteprise encounters an Illyrian ship and learns it's carrying spare parts necessary to fix the damages, but won't barter for them, he must abandon his ethical code and physically lay claim to the parts.
The Enterprise settles into port with Degra's ships while recooperating from its intense fight with the Xindi. Archer must convince Degra, however, that the Xindi superweapon Degra has created is going to be used within days and that humankind is an ally. Trip, meanwhile, is given the task of memorializing one of the fallen crew for the loved ones.
While attempting to reach the Xindi Council, the Enterprise finds a version of itself from a century into the future, brought on by an error during their travel through a wormhole. The descendants of the Enterprise, Lorian and Karyn, then try to help the current crew achieve success in their mission by ugrading the Enterprise's warp capabilities.
The Enterprise manages to make it to the chamber of the Xindi Council, where Hoshi helps Archer communicate with the council to let it know that the Sphere Builders have taken advantage of the Xindi to mastermind the superweapon and that Earth must be spared.
With the Xindi weapon set to be activated and ready to hurl towards Earth, Archer must make allies of the Xindi.
Archer heads a crew to stop the Xindi weapon from landing on Earth, dangerously racing to disarm the weapon from the inside. Meanwhile, the Enterprise's showdown with the Sphere Builders is inevitable.