From a Joss Whedon interview conducted back in 2005
Could Serenity take place in the same universe as Buffy but the monsters were taken care of long ago?I think you could make an argument for it, but I wouldn’t. The only thing we ever thought of doing is having a drunken and very miserable Spike at a bar just sitting there going, ‘Nothing changes. Trust me, nothing changes.’ That would’ve been in our decadent era. That would have been like season six. But no, I have to think about them as totally separate because they have different sensibilities and they have different sets of rules. It’s very important that Serenity be grounded. I had to go into outer space to come back down to earth but Buffy was a fantasy, a metaphor for rites of passage of our lives and Serenity is something else.