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.
Best recognized by his moniker Picchio, during his club tenure, De Sisti played for his native town club A.S. Roma on two occasions (1960–65, 1974–79), and ACF Fiorentina (1965–74), securing numerous domestic and international championships with both clubs. He made his debut in Serie A with Roma in a 2–1 away loss to Udinese, on 12 February 1961, where he observed the team's prominent player and mentor Juan Alberto Schiaffino during his initial stint at the club.