Eccentric director Terry Gilliam lined up Depp and Jean Rochefort to appear in the film back in 2000, and his attempts to make The Man Who Killed Don Quixote were chronicled by filmmakers Keith Fulton and Louis Pepe in 2002 movie Lost in La Mancha.
The filming of the oddball epic was set back by scheduling and financial issues and weather-damaged sets, but Gilliam has always been adamant the project will go ahead with Depp on board.
Rochefort pulled out of the movie after suffering a herniated disc - and now the Pirates of the Caribbean actor has followed suit, due to scheduling conflicts.
Gilliam, 68, says, "I can now honestly say that I'm not working with Johnny on Don Quixote. He's booked himself up on a lot of other films.
"I wanted to shoot Don Quixote next spring. He said he's not available and we have both agreed that I'm going to die soon, so it would be nice to get this film under my belt.
Depp was among the movie stars who stepped in to help Gilliam complete his film The Imaginarium of Doctor Parnassus after Heath Ledger's death last year (08).