The pint-sized pair's publicist confirmed the news to Entertainment Tonight, but would not comment on the reasons for the split.
Danny, 67, and Rhea, 64, met in 1971 after one of the Batman Returns actor's off-Broadway shows in New York.
They went on to play lovers in the '70s series Taxi, and acted together in just one film, 1996's Matilda.
Danny's film career took off in movies like Twins and Get Shorty, while Rhea became a household name in the '80s sitcom Cheers.
The pair own a production company, Jersey Films, making some of the biggest films in recent times, including Pulp Fiction, Erin Brockovich, Out of Sight and Reality Bites.
The couple have three children: Lucy, 29, Grace, 27, and Daniel, 25.
And we thought it would be forever! Check out the other cute celeb couples we really don't want to break up:
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