There will be spoilers. You have been warned.
The first hint came a few episodes before (A Spy in the House of Love). It was a small detail and may not have even been on purpose: while sewing up Dewitt’s bullet wound, Dr. Saunders was wearing blue gloves. Just like the men with blue hands who torqued River’s brain in Firefly. I’m by no means suggesting that Whedon set this up or that it even means anything. It could be just my writer’s brain putting details together and making phantom connections. But, suppose, 500 years from now, the Alliance, in an attempt to make their perfect assassin, recreates the brain wiping tech from Dollhouse? River, an early test subject of Topher’s pentupple great grandson, (in spirit, anyway) preforms an imperfect wipe and upload of River. She retains her mind, though it’s fractured by the new knowledge and skills they haphazardly copied onto her brain. She is then rescued by Simon. Cue Serenity.
During Epitaph One, we learn that the world has pretty much ended sometime between 2009 and 2019. China sent out a robocall to a million people, imprinting them as killers. Other uncounted millions have been wiped by random broadcasts of the remote wipe signal that turned Echo into her blank state in the middle of a heist (Gray Hour). we don’t know what sort of a state of affairs mainland China is in but the US, if not every other country, have become unwilling participants in a Mad Max fan film. We could surmise that China is doig just fine and did this as a way to takeover th eowlrd. It is,a fter all, much easier to use the Dollouse tech to turn half your enemies into mindless killers and th eother half into empty heads and just let them do each other in. Wait a few years for the fires to burn themselves out, then waltz in and gobble up the resources left behind. Of course, global catastrophes rarely follow a script. Also, not everyone is turned into a butcher or blank active. As in all catastrophes, the wealthy and conencted can afford to escape the fate of the common man. And they escape by leaving the planet, which is now a festering depleted hellhole. And maybe even some of the actuals left on earth survive and manage to find an escape as well. Perhaps there are arks full fo refugees, some blank, others intact, who make it off world as well.
Years in the future, they find a new system of planets and start rebuilding civilization. technology is uneven but nowhere near as advanced in most areas as before, and with patchy knowledge of Earth That Was and what life was like there, they adopt a frontier attitude and set about rebuilding society. It’s more civilized on some worlds than others, but eventually, they start colonizing the outer moons and planets. After a few centuries, the refugees of the Earth Dollhouse destroyed find themselves living in the Verse.
Obviously this isn’t cannon, but it fits very neatly together.
* Epitaph One could also be a fine series finale, which is obvious as they wrote it not yet knowing if the show would be renewed for a second season. But. Even with a second or third season, it’s possible to lead up to that same story, which puts Joss Whedon’s Dollhouse in a unique position in modern American serial drama: it could very well be the first series to have an actual ending that makes sense and isn’t a cop out, open-ended nonending, or a recap of what went before.