The 49-year-old actress opens up to the media mogul ahead of the premiere of The Rosie Show - a chat show - that will air on the US cable channel OWN next month.
The two talk about O'Donnell's failed marriage in the latest issue of O, The Oprah Winfrey magazine.
'In the O'Donnell family, no one had ever been divorced,' the New Yorker says of her 2008 split from partner Kelli Carpenter.
She says the relationship started breaking down soon after she ended her daytime talk show, The Rosie O'Donnell Show, in 2002.
At the time the two women were raising their three adopted children - Parker, now 16, Chelsea, 14, and Blake, 11.
When O'Donnell turned her back on her TV career the couple had another child, Vivi, now eight.
Although they were adding to their family - and married in 2004 - the actress admits they had reached a turning point in their relationship and started drifting apart.
O'Donnell tells Winfrey: 'It wasn't clicking for either of us. We didn't like the same stuff.'
She said she liked to be in the pool or on her boat whereas Kelli preferred to play tennis at the country club.