The couple first met in 1970 when Rhea went to see an off Broadway play, The Shrinking Bride, which featured Danny.
They started dating soon after, and wed in 1981, going on to have three children – Jacob, 25, 27-year-old Grace, and Lucy, 29.
The couple worked together on Seventies series Taxi, and 1996 children's movie Matilda.
Together the couple founded movie production company Jersey Films, which produced films including Pulp Fiction and Garden State.
A representative for the couple confirmed the split, but no reason has been given.
Danny spent time in London this summer, when he appeared in a two-month run of The Sunshine Boys at the Savoy Theatre in the West End.
The 67-year-old played Willie Clark, a sharp-tongued aging man who has a bittersweet reunion with his former acting partner.