Six months after Alpha's reign of terror and with him still on the loose, Echo now begins randomly picking up flashes of past engagements which hampers her latest assignment when she weds a British businessman client who has ties to one of Ballard's open FBI cases. DeWitt makes Ballard an irresistible offer to join the staff of the Dollhouse, which he's more than happy to agree to. Meanwhile, Topher and his assistant Ivy become the target of Dr. Saunder's anger and aggression after she finds out that she is actually a former Active named Whiskey... imprinted with the real Dr. Saunder's mind. Elsewhere, Boyd takes on a risky venture outside and mixes business with pleasure when he asks Dr. Saunders out on a date. While Victor struggles to deal with his nearly fatal encounter with Alpha, Echo now has her old memories of 'Caroline' now mixed in with every imprint she now takes in and she willingly agrees to help Ballard to take down the Dollhouse from within. Elsewhere, a dogged senator, named Daniel Perrin,begins investigating the Rossum Corporation, the Dollhouse's main benefactor, in order to search for a cos piracy linking it to medical imprint tests.

Echo is imprinted with the memory of a mother with a newborn baby for Dollhouse's latest business client. Complications arise when, thanks to Topher's programming, Echo takes too strongly to motherhood due to her maternal instincts. Meanwhile, Senator Perrin escalates his investigation into Rossum Corporation over the imprint technology. Also, DeWitt pays a visit to the former active November (now in her real personality of Madeline Costley) where she has a dark agenda of her own.

A backer of the Dollhouse needs to talk to his nephew who was injured in a car accident. He wants to find some people who may have been abducted by his nephew.

The story of how Sierra came to the Dollhouse is revealed. And leads to a shocking outcome.

Echo is sent to Washington, DC to stop Senator Daniel Perrin before he can expose the Dollhouse's secrets. Adelle and Topher also travel to the Washington DC Dollhouse where they meet its genius programmer, Bennett Halverson, a woman with a mysterious past connection to Echo.

Echo and Bennett have a shocking confrontation in which she reveals the reason for her grudge against Echo, while Adelle goes head-to-head with Stuart Lipman, the ruthless head of the Washington, D.C. Dollhouse to lobby for Echo's safe return. Meanwhile, Topher sees double when he involves Victor in his espionage plans to hack into the DC Dollhouse computer to locate both Echo and Senator Perrin as they try to run from Perrin's wife Cindy, who is more connected than thought to the DC Dollhouse. Elsewhere, Perrin finds a surprising witness, former active Madeline, who agrees to testify against the Rossum Corporation, while Ballard slips away from an ambush to set his own agenda.

After her entanglements with Senator Perrin and the DC Dollhouse, Echo finds herself out in the world-at-large as she struggles to control her multiple memory downloads, as well as those of her original memory of Caroline. Unsure who she is, Echo/Caroline calls upon the only person she can remember; Ballard, when she lands in a jam in a small town in Texas involving an illegal Mexican immigrant woman whom gets jailed by the local sheriff. Meanwhile, Topher discovers the dangers of science that will have devastating effects on the future over abusing the Active's imprints, while Adelle engages in a power struggle with Matthew Harding for control of the L.A. Dollhouse, and Boyd gets a phone call from someone in particular over Echo's whereabouts.

When all of Echo's past romantic engagements are found murdered, Adelle and the rest of the staff of the Dollhouse fear that Alpha has returned to seek his revenge. Adelle begins to grow suspicious of Ballard who hopes to find allies in Boyd and Topher in his continuing secret plan to bring down the Dollhouse from the inside. Meanwhile, Alpha emerges from hiding and, using his new high-tech mind-wipes, he commands all of the Actives to turn against their handlers, leaving one member of the house permanently mind-wiped.

Victor's five-year contract with the Dollhouse elapses and he goes back out into the real world under his old personality of Anthony Ceccoli. But his past as a soldier fighting in Afghanistan (whom he was running from the first place) threatens his present with Sierra who remains behind at Dollhouse and is conflicted over Victor's absence. Meanwhile, Echo continues to keep an eye on the comatose Ballard, while Adelle slips into hopelessness over recent events. When Victor/Anthony is captured by a rouge military unit with ties to Rossum Corp. Echo is forced to recruit Sierra, under her real personalty of Priya, to help rescue Victor/Anthony while Boyd and Topher monitor and keep Adelle in check to avoid her finding out what is going on behind the scenes.

When Adelle fears that Echo's multiple mind imprints are making her a danger to her goals for Rossum, she has Echo sent to "the Attic" where we finally see the place in the Dollhouse where other mind-drained actives and other people are kept in limbo where Echo is forced to face her worst nightmare in order to survive the Matrix-type universe her mind is in, and only former Dollhouse rep Laurence Dominic is there to help her, Victor, and Sierra find a way out, as well as uncover the mystery to the Attic's origins. Meanwhile, Adelle forces Topher to find a way to restore Ballard's mind-wiped memory in order for some grand plan she has for Rossum.

With the Rossum conspiracy now fully revealed, Echo and her allies must now make their stand to stop the Rossum Corporation from enslaving the free world with their newest remote mind-wipe technology to take over the world. Topher meets up with Bennett Halverson when she is forcibly taken from the DC Dollhouse and brought to Los Angeles to help restore Caroline's past memory whom is the only one who can identify the two Rossum corporate heads. Echo will finally face herself as Caroline, even as Ballard struggles with the facts of his new existence as an Active, while he also brings in former active November/Millie back into the fold. The background story between Caroline and Bennett is revealed from three years earlier during Caroline's status as a student in Arizona. As Adelle tries to prepare an evacuation of the Dollhouse, an invasion is incurred by Rossum soldiers, just as Whiskey/Dr. Claire Saunders finally returns to the Dollhouse at the request of Boyd with some info for all involved... and a few surprises as well.

Forced to flee from the Los Angeles Dollhouse in the aftermath of the Rossum attack which claimed the lives of several, including Bennett, Echo and the survivors of the Dollhouse head out to Arizona to locate and shut-down the Rossum Corporation's mainframe computer system which is scheduled to go into active status for remote mind-wipes in global proportions. But the traitorous Boyd with Dr. Saunders/Whisky could be of a problem to all involved as well as a few more surprises for Echo.

In the year 2020, events finally come full-circle as Echo and the few surviving Dollhouse staff struggle to restore mankind after the devastating events seen in the first season episode, "Epitaph" that has turned 90% of Earth's population into mindless, kill-crazy zombies out to kill those not infected (called 'actuals') by the Rossum's remote mind-wipe system. In the meantime, fellow actuals, Mag, Zone, and the mind-restored Caroline set out to find the save haven that can save man-kind from total extinction.