The outspoken TV host characterized the Maleficent star as 'a f*ing lunatic' who had driven her husband to booze and pot as an escape.
In a segment about the shock split, which she tweeted out on Wednesday, Handler said: 'There are rumors that part of the problem was that Brad was allegedly drinking and smoking too much weed. I wonder why he would need to self-medicate.'
She went on: 'Maybe because he could have been spending the last 12 years at Lake Como hanging out with George Clooney and Matt Damon, instead of being stuck in a house with 85 kids speaking 15 different languages.'
'Oh yeah, because he married a f*ing lunatic,
Handler, 41, is a longtime pal of the former Friends star, 45, and was among the guests at her wedding last year to actor Justin Theroux.