The Butler, to be directed by Lee Daniels, will tell the story of White House butler Eugene Allen, who served eight American presidents.
Rumors of Whitaker's involvement in the film began last month, and now the actor has signed on to play Allen. Winfrey is tipped to play Allen's wife.
Fonda - who will be playing Nancy Reagan - announced the news via her blog, saying of Whitaker and Winfrey: "It is their story. But a number of well-known actors will be playing cameos as the various presidents and first ladies for whom he worked."
The 74-year-old actress also responded to criticism that she is too controversial to play the conservative Nancy Reagan, adding, "I am an actor, and I have no intention of allowing the political differences between us to colour my portrayal of her. I will not be disrespectful."
Other actors rumoured to be starring in the project as US presidents and first ladies are Liam Neeson, Mila Kunis, Hugh Jackman and John Cusack.
Fonda will next appear alongside Jeff Daniels in Aaron Sorkin's new HBO drama The Newsroom.
Watch Jane Fonda in the trailer for The Newsroom below: