Unlike his younger brother, Sandro Mazzola spent his entire career with Inter, scoring 116 Serie A goals for the club in 417 league appearances.

In 1964, Mazzola scored twice to help Inter defeat Real Madrid in the 1964 European Cup Final to help the club emulate cross-city rival Milan's feat of the previous season; he finished the tournament as the joint top scorer with seven goals.

His biggest achievement with the national side came in 1968, however, when Italy won the 1968 European Championship on home soil under manager Ferruccio Valcareggi, and Mazzola was named as a member of the Team of the Tournament for his performance.

[11][12] As the Italians had difficulty scoring during the group stage, and Mazzola had struggled to regain match fitness after coming down with a stomach flu, Valcareggi devised a controversial solution for the second round of the tournament, which he called the "staffetta" (relay), in order to play both players.

The match was billed as the battle between offensive and defensive football, but on game day, Valcareggi abandoned his staffetta policy at half time, with the score tied at 1–1, and decided to only use Mazzola until the very end of the match, due to the precarious physical state of several of his starting players following Italy's taxing semi-final victory.

Two of Italy's biggest technical stars were finally united together on the pitch, where many people believed they should have been all along, but it was too late; Brazil won the match 4–1 to capture the World Cup title, their third overall.

[2][4][7][13][14][15] Four years later, Valcareggi finally used the two players together at the 1974 World Cup, but the ageing Italian side underperformed and was eliminated in the first round of the tournament.

Known for his athleticism, defensive work-rate, and acrobatic ability in the air, he initially played as an offensive–minded central midfielder in his youth, known as the "mezzala" role in Italian, but was later primarily utilised as an inside-right under Herrera, a role in which he rose to fame, establishing himself as one of the best players in the world in his position; he was also used as a centre-forward, as a winger, as a main striker, or even as a supporting striker on occasion.

[2][4][7][15][17][18][19][20][21] Despite occupying a more withdrawn, creative playing role for much of his career, Mazzola was also known to be a prolific goalscorer as a forward, due to his eye for goal, and his powerful and accurate striking ability from both inside and outside the area, as well as his ability to time his attacking runs and get on the end of his teammates' passes, which enabled him to win the Serie A top scorer award in 1965.

However, Mazzola was most highly regarded during his prime for his outstanding pace, acceleration, and stamina, as well as his dribbling ability, agility, technical skills, and balance, in particular when running at full speed while in possession of the ball; his pace, combined with his excellent ball control and technical ability enabled him to beat defenders frequently during matches, both in one-on-one situations or when undertaking individual runs.

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