The Hot Tub Time Machine actor will replace Tobey Maguire in the adaptation of the 1995 Pete Dexter novel, Variety reports.
Maguire joined the film in May, but was forced to drop out due to scheduling conflicts with Baz Luhrmann's The Great Gatsby. The Spider-Man star will play the role of narrator Nick Carraway in the F Scott Fitzgerald adaptation.
The Paperboy centres on two brothers - a reporter and a college dropout - who try to save a wrongfully-accused death row inmate. Cusack will portray the prisoner. Matthew McConaughey and Zac Efron also star.
Nicole Kidman signed on to appear in the upcoming drama last month, replacing Modern Family star Sofia Vergara, who also had to leave the movie due to scheduling conflicts.
The Paperboy is due out in cinemas in 2012.