He made his debut on 24 May 2003, against Piacenza as a starter, as Milan rested the majority of its regular starting eleven in view of the 2003 UEFA Champions League Final won over Juventus four days later.

[5] The acquisition was a consequence of Juventus' striking vacancies caused by a season-ending injury to striker Fabio Quagliarella and the loan of Amauri to Parma.

Matri made his Juventus debut only two days later, playing in a league game against Palermo, ended in a 2–1 win for the Sicilian opponents.

On 5 February, Matri scored his first two goals for Juventus on his return to Cagliari, when he latched onto a Miloš Krasić pass and drove into the near corner for the first, and volleyed again for the second, choosing not to celebrate on both occasions.

On 2 June, Matri officially signed for Juventus on a permanent deal that saw the club pay the pre-agreed €15.5 million transfer fee.

[12] On 30 August 2013, AC Milan bought back Matri from Juventus for an €11 million transfer fee[13] on a four-year contract.

[17] Marred by injuries to strikers Giuseppe Rossi and Mario Gómez, Fiorentina signed Matri on loan from Milan in January 2014.

[18] Matri was acquired with the intention to fill the absence left by injuries to forwards Rossi, the leading scorer in Serie A at the time with 14 goals and German international Gómez.

[20] On 21 February, he made his debut in the Europa League round of 16 match against Esbjerg, scoring Fiorentina's first goal in a 3–1 away win.

[30] On 20 May, he scored the winning goal in extra time to give Juventus a 2–1 victory over Lazio in the 2015 Coppa Italia Final.

[33] On 28 August 2015, in a friendly against Real Madrid, he made one of football's shortest substitutions, coming on for only five seconds in place of Philippe Mexès.

[37] On 2 September 2019, on the last day of the summer transfer window, Matri joined newly promoted club Brescia on a single-season loan with the option for a second.

[43] On 29 March 2011, he made his international debut in the friendly game against Ukraine played in Kyiv, under manager Cesare Prandelli, coming on as a substitute for Giuseppe Rossi in the 61st minute, and subsequently scoring his first goal for Italy in the 81st minute, from a Sebastian Giovinco assist, in a match which Italy won 2–0.

Although he is primarily deployed as a centre-forward, he is also capable of playing on the wing, or even off another striker, in a more creative role, on occasion, due to his unselfish team-play, as well as his ability to drop deep, link-up with midfielders, and create space for his teammates.

As a striker, he is primarily known for his ability to time his attacking runs, and play with his back to goal, as well as his defensive contribution and willingness to press opponents off the ball.