[12] Destro scored 18 goals in the 2009–10 Campionato Nazionale Primavera Group Stage and played a few club friendly matches for the first team.

[18] The transfer became official on 20 July 2010, when Genoa purchased a preferential option to sign Destro in a co-ownership deal in June 2010.

In 2011, Destro left for Serie A newcomers Siena on loan for €1.5 million[22] with an option for a co-ownership deal.

Destro would replace the Liverpool-bound striker Fabio Borini, whom Roma just sold for €13.3 million.

[29] Roma finished a distant sixth in Serie A,[33] but did reach the final of Coppa Italia.

[36][37] [38] Destro then started playing regularly,[29] showing the goalscoring form from earlier in his career.

[29] Controversy followed the Cagliari game, during which Destro had punched defender Davide Astori but was not punished at the time by the referee.

However, the league authorities later imposed a three-match ban on Destro (which became four matches for accumulated yellow cards).

[41] Only Sergio Aguero and Lionel Messi had a better goal-per-minute ratio than Destro across Europe's top five leagues.

[42] Destro was the subject of intense transfer speculation during the summer of 2014, being heavily linked by the media with moves to Chelsea and Real Madrid.

[49] Destro was the highest earning player of Bologna that season with a net salary of €1.6 million.

[55][56] After leaving Empoli as a free agent at the end of the 2022–23 season, he re-joined the club on 29 August 2023.

[59][60] He was the member of under-17 team in 2008 Euro qualification along with then-Inter teammates Davide Santon, Luca Caldirola, and Michele Rigione,[61]) scoring one goal in two appearances.

[65] Eventually the Azzurrini lost 0–1 to Russia (line-up unavailable) and finished third after winning 1–0 against Belgium.

Destro was a regular member of the under-18/19 team, receiving a call-up against Ukraine,[71] but did not play[72] and missed a friendly tournament in Slovakia due to injury.

On 8 October 2010, he started the play-off match and partnered with Okaka up front in a 4–4–2 formation, scoring the opening goal by converting a Diego Fabbrini pass with a left-foot shot.

However, after losing winger Ezequiel Schelotto and fullback Lorenzo De Silvestri, Italy lost 0–3 to Belarus in Borisov.

[84] On 15 August 2012, he made his debut with the Italy national team, starting in a 1–2 friendly loss to England at Wembley Stadium.

An accurate finisher, he is known for his anticipation, as well as his ability to make attacking runs into the area and subsequently shoot first time.