After playing for several smaller Italian clubs, such as Renato Curi, Chieti and Perugia, he made his breakthrough during his two seasons as a left-back with Palermo, which earned him a move to defending Serie A champions Inter Milan in 2006.

At international level, Grosso made 48 appearances for Italy and scored the decisive late first goal against Germany in the 2006 World Cup semi-final.

Grosso made 108 official appearances for Renato Curi, scoring 47 goals as an attacking midfielder and left winger.

By now, he had been converted into a left wing-back by head coach Serse Cosmi and in his second season in Perugia, he maintained a starting position and made 30 league appearances, scoring four goals.

Palermo's first season in Serie A was very successful as the club managed a very impressive sixth-place finish, losing just nine matches and also qualifying for the UEFA Cup.

He was one of four Palermo players who made Marcello Lippi's 2006 FIFA World Cup-winning squad, but at the conclusion of the tournament, Grosso was sold to Inter Milan.

In July 2007, Grosso moved abroad and signed a four-year contract with Lyon of the French Ligue 1, after passing a medical and agreeing personal terms.

In his second season with Lyon, Grosso was limited to just 22 league appearances, partially due to injury, but was heavily linked with a move back to Italy during the 2009 summer transfer window.

[11] However, after Juventus lost numbers of players due to injury, Grosso and Hasan Salihamidžić were recalled for the first time, on 6 November.

[10] Grosso made his international debut with the Italy national team on 30 April 2003 in a 2–1 friendly away win over Switzerland, under head coach Giovanni Trapattoni.

Francesco Totti subsequently converted the decisive penalty issued by referee Luis Medina Cantalejo, as a ten-man Italy won the match 1–0 to advance to the quarter-finals.

[15][16][17][18] In 2010, Grosso sat down with an Australian media outlet where he said he did not stay on his feet because he was exhausted and "didn't have the strength to go forward", he said he "felt contact, so I went down" and "maybe I accentuated it a little bit".

[19] On 4 July 2006, Grosso scored the first goal against hosts Germany in the 119th minute of the World Cup semi-finals, with a curling left-footed strike beyond the reach of Jens Lehmann into the Germans' net from the edge of the box, which commentator John Motson would describe as "magnificent", while Grosso ran about screaming "Non ci credo!"

For the 2010 World Cup, he was called up to the pre-World Cup training camp alongside Juventus teammates Gianluigi Buffon, Giorgio Chiellini, Fabio Cannavaro, Nicola Legrottaglie, Mauro Camoranesi, Antonio Candreva, Claudio Marchisio and Vincenzo Iaquinta on 4–5 May,[29] and was included in the 30-man preliminary squad announced on 11 May.

[37] Grosso was appointed manager of Hellas Verona on 21 June 2018, signing a two-year deal at the newly relegated Serie B club.

[45] On 29 October 2023, prior to an away match against rivals Marseille at the Stade Vélodrome, Grosso suffered a facial injury due to shards of broken glass hitting his face after the Lyon bus was pelted with stones on its way to the stadium.

[47] Following a short tenure that saw Lyon failing to improve in its results and lying at the bottom of the league table, Grosso was ultimately dismissed from his coaching position on 30 November 2023.

A versatile footballer, regarded as one of the top Italian full-backs of his generation, he was also adept with accurate crossing ability, which even allowed him to be deployed as a winger or as an attacking wing-back on either flank throughout his career, despite being naturally left-footed.