Archer's old friend Emory Erickson, inventor of the transporter technology used by the Enterprise, comes aboard the ship to make an upgrade, but the crew soon learns that he plans to, in actuality, use the ship to try and find the son who disappeared as a result of a glitch in the transporter technology.
A bruised Archer, having saved Earth from the Xindi, mysteriously wakes up in 1940s Germany where, held captive by the Nazis and a group of uniformed aliens, he learns that aliens have helped Nazi forces launch an invasion on America. After breaking free, Archer teams up with a trio of American Resistance members to stop the aliens from bringing about the total destruction of America and curtailing the future of the world.
Archer utilizes Silik's help in tracking down the one who rewrote Earth's history and is now headed towards making a reality the destruction of all of history itself.
The crew of Enterprise heads home to Earth following its battles with the Xindi and the Temporal Cold War. Meanwhile, Trip and T'Pol head off to meet T'Pol's mother, T'Les.
The Enterprise team brings Dr. Arik Soong onboard to help locate his wayward creations, a group of genetically-enhanced human beings he made using stolen DNA.
Having escaped from Captain's Archer custody, Dr. Soong heads back to his old medical lab Cold Station 12, which is currently housing hundreds of the genetically-engineered human embryos which Soong plans to raise as Augments, the first wave of beings designed to supplant ordinary humanity.
The Enterprise crew chases through Klingon territory to stop Dr. Soong, who has ventured to a planet he hopes will serve as the home base for his Augment children. The Augments, however, turn on Dr. Soong and are soon attempting to instigate a war between Klingons and humans.
When the signs of a bomb attack on a Vulcan embassy point to the Syrrannites, a militant religious faction split off from the traditional Vulcan teachings, T'Pol and Archer must pursue the perpetrators through the Vulcan desert.
Archer and T'Pol come face to face with the Syrrannites after following them through the desert, where T'Pol confronts her mother, who has joined up with the rebel group. Meanwhile, the crew of the NX-01 is forced to grapple with the Vulcans' tactics, as their attack against Andoria threatens to pull Earth into a major war.
In the midst of a dispute between Andorians and Vulcans involving the NX-01, Archer, T'Pol, and T'Pau make their way to the Kir'Shara with a relic they believe holds original written messages sent from Surak to the Vulcans.
The Enterprise crew is the subject of an unwitting experiment conducted by aliens to see how humans respond to tragedy following the spread of a fatal virus across the ship.
On the way to a peace conference with the Andorians, the Enterprise finds itself under attacked by Romulans while shepherding Tellarite vessels carrying delegates.
As Malcolm and Tripp are stuck on the ship that is being controlled from afar by the Romulans, they must outmaneuver the cunning Romulans and keep the Tellarites and Andorians from declaring war on one another. Meanwhile, Archer attempts to protect his own crew while keeping the peace between the argumentative factions, but the killing of an alien from one of the factions further escalates the tension.
Archer journeys to Shran's home planet in an attempt to locate a species called the Aenar, a peaceful group which may have a connection to the Romulans and the recent destruction of several local space vessels. Meanwhile, Trip and T'Pol try to design a device which will override the Romulans' remote-controlled ship.
A group of Klingons kidnaps Dr Phlox and forces him to work on a cure for a genetically-engineered virus threatening the existence of the entire Klingon race. Trip readies to begin his next assignment on the inaugural trek of the starship Columbia. Meanwhile, Reed's interactions with a secret organization could have dire consequences for Archer and the crew, while T'Pol attempts a mind-meld to find Dr Phlox.
Archer uses the help of the Starship Columbia and its shipmates, Captain Hernandez and Trip, to go after the kidnapped Dr Phlox within Klingon turf, while Dr Phlox agrees to devise a vaccination that will help save the Klingon race. Meanwhile, Reed's further activities with a mysterious organization forces Archer to confront him for the truth.
After successfully arbitrating with the Orion Syndicate, Archer is surprised to find himself presented with a trio of slave girls as a token of appreciation.
An alternate version of the Enterprise finds the ship's goals more ruthless, with an alternate captain and Archer as the captain's villainous first officer heading up the crew. On a mission into the heart of enemy territory, this version of the Enterprise comes across a startling revelation.
The power mad Archer and his Enterprise crew utilize a ship known as the Defiant to stop a Tholian onslaught, after which time Archer sets his sights on overtaking Earth's Terran Empire.
While on Earth for an interplanetary peace conference, Archer and the Enterprise crew come across the dark plans of a radical human group called Terra Prime, who wish to reduce the alien population present on Earth, keeping humans as the dominant influence. Meanwhile, the radical group seems to know something about a baby they claim T'Pol and Trip are expecting, while Travis is pursued by a reporter with ties to his past.
Archer, Reed, and Travis continue their efforts to stop Paxton, a radical human leader who wishes to end the alien presence on Earth, from forcing the implementation of his demands through the destruction of Starfleet Command. Meanwhile, T'Pol and Tripp, held captive by Paxton, find themselves intrigued with a baby girl that was created using DNA from each of them.
After six years have passed, the Enterprise crew returns to Earth, with the ship now retired from action, and the interplanetary alliance is solidified with the signing of a Federation charter. At Shran's request, the crew's final mission takes them on a perilous journey to find and retrieve his abducted daughter.