During his career, Serena played for a number of Italian clubs: Montebelluna, Inter, Como, Bari, A.C. Milan, Juventus and Torino. Born in Montebelluna, in the province of Treviso, he spent his youth playing with his hometown side's youth academy. After making his professional debut with the Montebelluna senior team in Serie D in 1977, and scoring 9 goals in 29 appearances during his debut season, Serena first joined Inter the following season in 1978; he made his Serie A debut later that year, on 19 November, in a 4–0 home win over Lazio, marking the occasion with his first Serie A goal, and also making another league appearance later that the season. Although he initially won the 1981–82 Coppa Italia during his first spell with the club, he mainly served as a back-up, and was initially loaned out to several other Italian sides: he spent seasons on loan with Como, Bari, cross-city rivals Milan, and Torino. He also enjoyed a successful two-season spell with rivals Juventus between 1985 and 1987, scoring 21 Serie A goals in 51 appearances, as well as winning the 1985 Intercontinental Cup and the 1985–86 Serie A title; in total, he scored 36 goals in all competitions for the Turin side in 71 appearances. Serena enjoyed greater success after returning to Inter for his second spell in 1987. 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. He also later won the 1989 Supercoppa Italiana and the 1990–91 UEFA Cup during his second spell with the club.