The 60-year-old actor would join Charlize Theron and Amanda Seyfried in MacFarlane's next movie, said Hollywood reporter.
MacFarlane wrote the script with Alec Sulkin and Wellesley Wild and will direct and produce with Scott Stuber and Jason Clark. A May production start is planned.
The film follows a cowardly sheep farmer (MacFarlane) who chickens out of a gunfight and sees his girlfriend (Seyfried) leave him for another man. When a mysterious woman (Theron) rides into town, she helps him find his courage.
Giovanni Ribisi also recently boarded the project when Jonah Hill passed it.