Best known by his nickname Picchio, during his club career, De Sisti played for his hometown club A.S. Roma on two occasions (1960–65, 1974–79), and ACF Fiorentina (1965–74), winning several domestic and international titles with both clubs. He made his debut in Serie A with Roma in a 2–1 away defeat to Udinese, on 12 February 1961, in which he observed the team's star player and mentor Juan Alberto Schiaffino during his first spell at the club.
De Sisti is most famously known as Picchio, and during his club career, he played for his hometown club A.S. Roma twice (1960–65, 1974–79) and ACF Fiorentina (1965–74), earning several domestic and international titles with both teams. He made his Serie A debut with Roma in a 2–1 away loss to Udinese on February 12, 1961, where he watched the team's star player Juan Alberto Schiaffino during his first period at the club.