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After becoming CEO of Hyperion, Rhys finds himself forced into the unfortunate position of indebted to Handsome Jack. After Jack unveils his Jack model endoskeleton robotic suit and a plan to shove them – and his AI – into any disobedient Hyperion employee, dead bandit, or general corpse, Rhys flees his office.
Hyperion, in the meanwhile, is put on lockdown. Rhys, in an attempt to shut down Handsome Jack, shuts down Helios' main power source. Sasha and Fiona capture their captors and try to escape through the mayhem, only to be confronted by Handsome Jack as they try and get to the caravan. August appears and shoots down all of the monitors, temporarily evading Jack. The group move onward toward the bay and are greeted by Finch and Kroger. Finch lures Gortys into the caravan and Kroger pulls out guns on the crew, saying that there had been a change of plans. As a result of a brawl, Sasha departs in the caravan alongside Finch, Kroger and Gortys, and Fiona is left to try and escape, which she succeeds in doing through an escape pod.
When Fiona comes to after crashing on Pandora, Gortys has been completed and activated. The Traveler is unleashed upon Pandora, but she is helpless to fight it. Vallory dies by the hands of the Traveler as she attempts to kill Gortys, who begs to be destroyed in order to seal the Vault and the Traveler with it. Gortys cries out for Fiona to grab the rocket launcher and destroy the yellow orb, which she fails to do without the assistance of Sasha.
Meanwhile in the old, destroyed city of Opportunity, Rhys and Jack battle one another; Jack wishes to kill Rhys for turning his back on him, and as such, forces his robotic arm into a protruding piece of metal after Rhys breaks free of Jack's attempt to strangle him. In order to shut down Jack completely, Rhys begins to tear himself apart - first by removing his arm, then by removing the hole on the side of his head with a jagged piece of glass, and finally by plucking out the ECHO eye. Handsome Jack then falls to his knees and begs Rhys to save him out of fear of the loneliness of oblivion, but Rhys pulls the ECHO eye out entirely and is left with the decision to keep him trapped in the ECHO eye, or to crush it. Afterward, he blacks out.
Back in the present, a captive bandit shows up, escorted by Kroger. The bandit was meant as a trade for Fiona and Rhys, but the stranger kills Kroger. The bandit raises his hand to seemingly aim snipers at the trio before kicking down the stranger and releasing Rhys and Fiona from their tape prisons. After removing his mask and tying up the stranger to prevent him from doing harm, the bandit is revealed to be Vaughn who had been nursed back to health by Cassius. The sniper lasers are also revealed to have been laser pointers for the sake of intimidation.
Vaughn escorts Rhys and Fiona to the base, which is revealed to be forged from the remains of Helios. Vaughn was deemed the leader of a band of Hyperion refugees named the Children of Helios since they had come out "like newborns". They all bow to Rhys because he was the one that released the refugees from the chains of corporate bondage, and they even have a decapitated Handsome Jack statue with Rhys's name etched on it in red marker to further revere him.
Once inside the base, Fiona and Rhys with the back-up of Vaughn begin to question the stranger about who he is and why he captured them. The stranger is revealed to be Loader Bot, who had saved Rhys and Fiona from dying in the destruction of Helios. Loader Bot explains that he needed both Rhys and Fiona to put together Gortys again so they could get into the Vault and defeat the Traveler, saying that now they could defeat the monster since they had more firepower and more allies. Rhys and Fiona agree, and Vaughn joins in with the rest of the Children of Helios.
After choosing three other possible people to join you as Vault Hunters (August, Felix, Athena, Springs, Zer0, Cassius, or an "unknown" character that you can purchase with money that you've gained within the game which is revealed to be Claptrap), a plan is set out. Sasha and Fiona are to set up in the caravan to soar into the Traveler's crystalline stomach so they can explode the device that causes the Traveler to teleport. In order to get them to do that, Rhys must be a motivational speaker and get Gortys to move in such a way that the Traveler is set up for Sasha and Fiona to enter. The rest of the group would flank from the sides and do additional damage, but Vaughn would stay back in the base and prime a moonshot for when Fiona and Sasha would disable the teleportation device.
Not everything goes to plan. Vaughn sets off the moonshot too early and profusely apologizes. Gortys, at first, refuses to cooperate because she felt as if the plan wouldn't work since it didn't last time, but Rhys ends up encouraging her. He becomes the co-pilot and begins to fight the Traveler in order to cause it to teleport toward Fiona and Sasha's position. When that succeeds, the pair soar with the caravan into the crystalline stomach, only to find that the device is protected by two Guardians. A lack of gravity allows them to clamber up the rocks and outplay the Guardians in order to attach the charge.
In the meantime, everyone else has been entered as co-pilots and work to fight the Traveler. However, the Traveler hulks toward the Children of Helios base, causing Vaughn to panic. Sasha and Fiona enter the caravan and begin to boost their way out, and when they feel as if they are a safe distance away, they try to detonate the explosion but learn that they are out of range. Sasha decides to take the detonator and depart from the caravan in order to go back and detonate the explosion. Fiona escapes in the caravan, and the explosion goes off moments later.
With the moonbeam primed once more, Vaughn fires it which gives Gortys enough time to conjure a plasma sword which cuts through the Traveler and incurs the final blows. Gortys releases the Vault Hunters and the group celebrates, but not for long. They discover Sasha's body shortly afterward, revealing that she is alive but doesn't have much time. Rhys cries over her and she questions him to which he says that he had heard that some tears worked as cures. Sasha denies this as fact. If Fiona kept Felix's gift, Sasha will ask for it. The gift is revealed to be a watch with the phrase "time heals all wounds" engraved on the back.
Sasha appears to die, but after a few moments, she claims that she isn't dead yet. The watch hovers over her and lifts her body, glowing red. It is revealed to have healing properties and heals her to almost full health before it drops her and breaks her arm. Everyone crowds around her, thankful for her life, before separating and going to loot what the Traveler dropped.
Rhys and Fiona split from the main group and head toward the Vault itself, racing each other. Once they arrive, Fiona presses the issue of Rhys's potential crush for Sasha. After getting the conversation out of the way, the pair enter the Vault and climb up, talking about their adventure and their future plans. Once reaching the chest, they both say that they should open it together as it would only be fair (mirroring their conversation at the end of Episode 1), and disappear together once opening it.