Serena started his playing career with Mestre of Serie C2, then become Venezia following a merger. He was signed by Juventus in 1989, and made four league appearances with the bianconeri. He then played for Monza and Verona before signing for Sampdoria, where he played for three years. In 1995 he was signed by Fiorentina, and in 1998 by La Liga club Atlético Madrid, where he made 35 appearances with 3 goals and gained a spot in the national team, making his one and only appearance with the azzurri on 5 September 1998 in a 2–0 away win to Wales. He then returned in Italy to play for Parma but moved to Inter soon after during the winter transfer market (exchanged with Paulo Sousa). With the nerazzurri jersey, he made only 15 appearances in three seasons, mainly because of the several injuries he experienced during his years at Inter and forced him to retire.
In 2007 he became the Venezia youth team coach, also getting involved in obtaining a coaching licence. On 11 March 2008 he was unveiled as new Venezia head coach, replacing Salvo D'Adderio. He was sacked a few months later, on 11 November, due to poor results. He was recalled on February 2009, with Venezia placed in the league bottom, and managed to bring his club out of the relegation zone.
This attracted interest from Serie B club Mantova, who appointed him as new boss for the 2009–10 season. Mantova finished 3rd bottom of Serie B and were relegated. However, due to financial difficulties, their entry to Lega Pro Prima Divisione was rejected and the club folded.