The two actors have signed on to Scott Alexander and Larry Karaszewski's latest biopic, reports Deadline.
Witherspoon and Reynolds will play Margaret Keane and Walter Keane, the couple who created the large-eyed children paintings that were popular in the 1950s and '60s.
The couple eventually split, with the shy Margaret proving that, contrary to popular belief, she was the artist of the pair.
The Ed Wood and Man on the Moon writers have been working on the project for several years.
"We are ecstatic to have this dream cast for our dream project," said Alexander and Karaszewski in a statement.
"Walter is a larger-than-life antihero - charming, funny, dangerous, and a little crazy. Ryan will knock it out of the park. As for Reese, she will be perfect as Margaret - soulful, decent, transforming from vulnerability to learning to fight for herself."
Ed Wood director Tim Burton is producing with Lynette Howell and Jamie Patricof, whose Electric City Entertainment was responsible for reviving the project.
Kate Hudson and Thomas Haden Church were formerly attached to star in the film.
Burton, Alexander and Karaszewski were previously rumoured to be working on an Addams Family movie.