It would mark the Broadway debut both for Franco, 35, and O'Dowd, 34, the Irish actor who shot to fame as Kristen Wiig's policeman love interest in Bridesmaids and as Thomas John on Girls.
Franco, an Oscar nominee for 127 Hours, has officially signed on to play George, while O'Dowd is still in negotiations to play his mentally limited brother Lennie, reports the New York Times.
Of Mice and Men tells the story of two migrant field workers in California during the Great Depression. John Steinbeck, who published the novella in 1937, adapted it for the stage that same year. This will be its second Broadway revival, following a production in 1974 starring Kevin Conway and James Earl Jones.
Anna D. Shapiro, who won the Tony Award in 2008 for directing August: Osage County, will direct the new Of Mice and Men.