[13] Due to his maturity, tenacity and leadership on the pitch, on 15 March 2006, De Rossi wore the captain's armband for the first time in an UEFA Cup match against Middlesbrough.

[7] Despite earning several cautions and a reputation as a hard-tackling player during the 2005–06 season, on 19 March 2006, De Rossi was praised by referee Mauro Bergonzi for fair play.

[14] Roma were trailing 1–0 in a Serie A match against Messina, when De Rossi scored a goal from a header, which had been deflected off of his hand; Bergonzi did not see the incident and allowed the equaliser to stand.

[16] In the 2006–07 season, De Rossi continued to be a decisive player for the team,[7] scoring from 40 yards against Fiorentina on 5 November 2006, with Sébastien Frey in goal.

[19] The following season, under manager Luciano Spalletti, Roma won the Supercoppa Italiana over Serie A champions Inter, with De Rossi scoring the decisive goal from a penalty in a 1–0 victory in Milan on 19 August 2007.

On 4 February 2011, however, De Rossi was elected the best Italian Athlete of the Year, alongside swimmer Federica Pellegrini, by the Foreign Press Association in Italy.

[39] In the game against Napoli, De Rossi played a crucial role in the first half when the score was still 0–0; Roma went on to win through two Miralem Pjanić goals.

[40] He captained Roma after Francesco Totti was sidelined with a hamstring injury, playing three successive draws against Torino, Sassuolo and Cagliari, and slipped to second place, one point behind Juventus.

[41] Due to this series of draws, De Rossi admitted that he was not sure whether Roma could seriously challenge for the Scudetto in the long run, believing that both Juventus and Napoli had stronger squads with greater depth.

[50][51] On 28 May 2017, De Rossi scored in a 3–2 home win against Genoa, which enabled Roma to finish in second place in Serie A and secure a Champions League group stage spot for the following season.

[77][80] A few weeks after returning from Greece, De Rossi earned his first cap with the Italy senior squad on 4 September 2004, scoring on his international debut in a 2–1 win against Norway in a 2006 World Cup qualifying match, at the age of 21.

[82] De Rossi was named to Marcello Lippi's 23-man Italian squad for the 2006 FIFA World Cup,[83] producing a notable performance in Italy's opening 2–0 win against Ghana, but also picking up a booking in the tenth minute.

[87] After having been disqualified for four matches, De Rossi returned to the pitch in the World Cup final against France, coming on as a substitute in the 61st minute, for Roma teammate Francesco Totti.

[89] After Totti decided to retire from international football following Italy's victorious 2006 World Cup final, De Rossi was also given the honour of wearing the number 10 shirt.

[102] In Italy's opening fixture of the competition on 15 June, De Rossi scored against the United States in the 71st minute with a low long-range strike.

[105] Due to his performances and dedication at international level, De Rossi was tipped by several in the media to be a possible candidate for Italy's captainship after the retirement of Fabio Cannavaro.

His ability to perform well and score in important matches and his pivotal role in breaking down the opposition's play as a box-to-box midfielder won him admiration from the Italian fans.

Indeed, De Rossi scored several crucial goals for Italy in their Euro 2008 and 2010 FIFA World Cup qualifying campaigns; at the international level, De Rossi's goal ratio was much greater than at club level during this period, as he played mainly as a defensive midfielder for Roma, whereas he was able to play in more advanced positions for Italy, due to the presence of Gennaro Gattuso in the team's holding midfielder role.

[117] Due to Andrea Barzagli's pre-tournament injury, however, De Rossi played as a central defender in a three-man defence in Prandelli's 3–5–2 formation, alongside Giorgio Chiellini and Leonardo Bonucci, during Italy's opening two group matches of the competition against Spain and Croatia, which both ended in 1–1 draws, receiving praise for his performances in the media; he was temporarily replaced by Thiago Motta and Riccardo Montolivo alongside Pirlo and Marchisio in Italy's three-man midfield.

[123] In June 2013, De Rossi was called up for 2013 FIFA Confederations Cup in Brazil, and he scored in a 4–3 win over Japan in Italy's second group game.

[124] Italy eventually finished the tournament in third place after a penalty shoot-out victory over Uruguay in the bronze medal match, in which De Rossi appeared.

[125] De Rossi was included in Prandelli's final 23-man squad for the 2014 World Cup in Brazil, the only Roma player to be selected to the national team.

[129] De Rossi also participated in the second group match against Costa Rica,[130] but was unable to play in Italy's 1–0 loss against Uruguay[131] due to injury.

[132] On 4 September, under Italy's new manager Antonio Conte, De Rossi wore the captain's armband in a 2–0 friendly home win over the Netherlands in Bari, also scoring a goal from a penalty.

[133] On 16 November 2014, in a UEFA Euro 2016 qualifying match against Croatia at the San Siro in Milan, De Rossi earned his 100th cap in a 1–1 draw.

When he was asked to warm up late on during the game, he appeared to protest the decision and instead pointed angrily at Napoli forward Lorenzo Insigne, a player whom the national side's manager, Gian Piero Ventura, had neither started nor brought on, in spite of pressure from the Italian media and criticism from the fans; following the match, De Rossi commented on the incident, stating, "We have this tendency to warm up three at a time, then after five minutes we change and another three go.

[168] His role has also been likened to that of a metodista ("centre-half," in Italian football jargon), due to his ability to dictate play in midfield as well as assist his team defensively.

[178] In September 2022, De Rossi was admitted to the UEFA Pro yearly coaching course organized by the Italian Football Federation, together with fellow 2006 FIFA World Cup winners Marco Amelia, Andrea Barzagli and Alessandro Del Piero.

[185] On 18 September 2024, after failing to achieve a single win in the first four games of the season, Roma announced the dismissal of De Rossi from his managerial duties.

[194] De Rossi was chosen as a Pringles spokesperson for Euro 2008, along with other top European football players such as Thierry Henry, Fernando Torres, Alexander Frei, Philipp Lahm and Michael Owen.