[2] During his career, Serena played for numerous Italian clubs, including Montebelluna, Inter, Como, Bari, A.C. Milan, Juventus and Torino.

His best season with the Milan-side came during the 1988–89 campaign under manager Giovanni Trapattoni, when he won the Scudetto with Inter with a record 58 points (the club's thirteenth Serie A title overall), and was crowned top scorer of the league, scoring 22 goals.

[5][6] In 2005, Serena and Christian Vieri were the only footballers to have played for both of the rival teams of Turin and Milan,[5] The former is also one of six footballers to win the Serie A title with three clubs, a feat he managed with Juventus, Inter, and Milan, whilst the others to have achieved the same feat are Giovanni Ferrari, Filippo Cavalli, Pietro Fanna, Sergio Gori and Attilio Lombardo.

[5][7] At the 1990 World Cup in home soil, Serena scored with a header on his 30th birthday in Italy's 2–0 round of 16 win over Uruguay on 25 June.

[6] In the semi-final match, he left the pitch in tears after he missed a crucial spot kick in the semi-final shoot-out against Argentina, with the goalkeeper Sergio Goycochea saving the ball to his left, a game the home nation lost on penalties following a 1–1 draw after extra-time.

[7] Serena was a fit, strong, dedicated, hard-working, and athletic centre-forward who excelled in the air; a former defensive midfielder and a basketball player in his youth, he was known in particular for his powerful and accurate heading ability, due to his height, strength, and elevation, as well as his positional sense, and his tenacious, intelligent, and physical style of play with his back to goal, which enabled him to shield the ball from defenders, create space in the area, anticipate opponents, and win aerial challenges, despite his lack of notable pace.