In 2004, Burdisso moved toInter Milan ofSerie A, signing a four-year contract.[5] However, he missed almost all of the 2004–05 season after Inter allowed him to return to Argentina to support his daughter Angela, who was fightingleukemia.[6] He returned to action in October 2005 when he played as a second-half substitute in the 5–0 hammering ofLivorno.[7] On 31 August 2006, he extended his contract until 2009.[8] On 8 September 2006, four days afterGiacinto Facchetti died, Burdisso was given the number 16 jersey for the retirement of Facchetti's beloved number 3 jersey.[9]
Burdisso enjoyed his most prolific campaign during the2006–07, when he was named the Coppa Italia top scorer with 4 goals jointly with four other players. This also included his first career brace on 29 November 2006 in the 4–0 victory againstMessina. He again scored twice on 24 January 2007, in the 3–0 victory againstSampdoria. Inter eventually made their way to thefinal, where they faced Roma; Burdisso played in the second leg which Inter won 2–1, but they lost the trophy 7–4 on aggregate.[10] In addition to that, he also scored two goals in the championship which ended in conquest.
During theChampions League tie betweenValencia and Inter on 5 March 2007, a fracas broke out between players of the two teams. Burdisso suffered a broken nose from a punch in the face from Valencia defenderDavid Navarro.[11] As punishment for his part in the brawl, Burdisso was handed a six-match ban from all European club competitions, with an additional two match suspension. Navarro was sentenced to a seven-month ban from domestic, European and international matches.[12] The match at theMestalla ended in a goalless draw, which sent Inter out of competition on away goal rule.[13]
Burdisso eventually returned to duty on 12 March 2008 in the second leg of theChampions League match againstLiverpool, but was sent off in the 60th minute after receiving his secondyellow card of the game.[14] With Inter, he played left and right back and central defender as a key member of the squad in three different competitions.
Burdisso left the club in August 2009 after playing 139 matches and scoring eight goals in all competitions, winning nine trophies in the process.[15]
On 22 August 2009, Burdisso was signed byRoma on loan, which offered him €3.04 million (gross) salary per year.[16] He played the opening match of the league on 23 August. He scored his first goal for Roma on 20 December 2009, opening the scoring in a 2–0 win overParma.
Burdisso was then signed by Roma permanently on 28 August 2010 for an €8 million transfer fee. He signed a four-year contract, in which he would earn €3.8 million (pre-tax) his first year, increasing to €4.5 million pre-tax in the next three years.[17]
He scored his fifth goal—first in the2011–12 Serie A—for Roma againstMilan on 29 October. Roma lost that game 3–2. On 15 November 2011, he suffered a serious injury to his left knee which will force him out of action for six months.
In 2007, Burdisso expressed his desire to finish his career atBoca Juniors.[18]
In2012–13 season underZdeněk Zeman, Burdisso was relegated to the bench. He played only eight matches in the first part of the season, scoring the opener in a 4–2 win over Milan. Prospects in the starting XI remained dismal after the arrival of new managerRudi Garcia, typically serving as third-choice centre-back behind startersMehdi Benatia andLeandro Castán.
On 15 May 2006, Burdisso was named as a squad member for the2006 FIFA World Cup by his former U-20 coachJosé Pekerman, going on to play in all three group matches. He also played for Argentina in theCopa América 2007, where the team went on to reach the final.
On 15 November 2011, Burdisso injured his left knee during a World Cup qualifying match againstColombia. During a disputed ball withJames Rodríguez, Burdisso partially tore his left knee ligaments, with initial assessments predicting a recovery period of six-to-eight months.[21]
Retiring in the summer 2018, it was confirmed at the end of December 2018, that Burdisso had been appointed sporting director of his former club,Boca Juniors, signing a deal until December 2020.[25] However, he resigned from the position at the end of 2019.[26]
On 6 July 2021, Burdisso was appointed technical director ofFiorentina.[27] He left the position at the end of 2023-24 season.[28]