Gilliam confirmed the casting news exclusively to Empire Online during the weekend.
The filmmaker first tried to shoot the movie a decade ago but the production was sidelined by weather and budget woes, as well as an ailing leading man in Jean Rochefort. The setbacks were chronicled in a popular documentary called "Lost in La Mancha."
Depp had hoped to appear in the second attempt at "Quixote," but his commitment to the "Pirates of the Caribbean" franchise poses a conflict with Gilliam's planned September start date for "Quixote," Empire Online said.
Robert Duvall is to take over the role played by Rochefort in Gilliam's original "Quixote" movie.
"Robert Duvall is one of the greats, no question -- and he can ride a horse!" Gilliam told the Web site. "And Ewan has gotten better over the years. He was wonderful in 'The Ghost.' There's a lot of colors to Ewan that he's not been showing recently and it's time for him to show them again. He's got a great sense of humor and he's a wonderful actor. He's wonderfully boyish and can be charming -- when he flashes a smile, everybody melts. He wields it like a nuclear bomb!"