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. He enjoyed his most successful period with Fiorentina, which included a league title in 1969, the club's second overall, before returning to Roma in 1974. He won the Coppa Italia with both clubs, in 1964 and 1966.