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.

[1][2] Internationally, De Sisti earned 29 caps and scored 4 goals for the Italy national football team between 1967 and 1972, making his debut on 1 November 1967, in a 5–0 home win over Cyprus in a UEFA Euro 1968 qualifying match.

He later played in the European championship-winning team at Euro 1968 on home soil, appearing in the 2–0 final replay victory over Yugoslavia in Rome, at the age of 25.

[5] A creative and technically gifted deep-lying playmaking midfielder, who is regarded as one of Italy's and Roma's greatest ever playmakers, De Sisti was known for his simple yet efficient style of play; this involved him constantly looking for spaces, playing many short and accurate passes on the ground, and taking very few touches of the ball, in order to retain possession, reduce the chance of errors, and set his team's tempo.

[1][2][6] On 3 July 1968, De Sisti founded the Italian Footballers' Association (AIC), in Milan, along with several fellow footballers, such as Giacomo Bulgarelli, Sandro Mazzola, Ernesto Castano, Gianni Rivera, and Giacomo Losi, as well as the recently retired Sergio Campana, also a lawyer, who was appointed president of the association.