[10] His debut occurred on 20 November 2004 in a Coppa Italia match against Lecce, where he was sent-off in 91st minute for conceding a penalty after a foul on Mirko Vučinić; since Udinese had used all three substitutions, striker David Di Michele entered in goal in his place.

[28] On 16 August 2011, he played his first ever UEFA Champions League match against Arsenal, in the first leg of the play-off round, being beaten by a Theo Walcott 4th-minute goal in a 1–0 away loss at Emirates Stadium.

[31] Udinese and Handanović were unbeaten in their first seven Serie A games, and only conceded one goal in that period, which was the best defensive record in top European leagues at the time.

On 17 August, Handanović suffered a meniscus injury[40] that delayed the start of his Serie A campaign until 16 September, in a 2–0 road win over Torino.

[41] Handanović kept crosstown rivals AC Milan at bay in his first Derby della Madonnina appearance on 7 October, won 1–0 by Inter.

[44] Inter were held to a 1–1 draw in the second derby encounter on 25 February 2013, but Handanović was noted for performing several saves against Milan striker Mario Balotelli.

[4] After the end of 2012–13 season, thanks to his solid performances, Handanović was selected in Serie A Team of the Year for the second time in his career, being the goalkeeper with most appearances.

[56][57][58] On 20 October, during the league encounter against Torino, he received his second-ever career red card for a foul on Alessio Cerci in the 5th minute; Inter however endured and drew 3–3.

He played as a starter in Javier Zanetti's last competitive match at San Siro, in which Inter defeated Lazio 4–1 to secure a place in Europa League play-offs for the next season.

Inter opened the 2014–15 Serie A season with a disappointing goalless draw against Torino, with Handanović stopping a penalty kick from Marcelo Larrondo.

[10] At the end of the season, it was reported that Handanović was the target of Premier League side Manchester United,[67][68] but his agent turned down this opportunity by saying that his client will not move to the club.

[70] On 27 September 2015, in his 300th Serie A match, against Fiorentina, Handanović made perhaps his worst appearance by giving away a 3rd-minute penalty scored by Josip Iličić, later being beaten three times by Nikola Kalinić in an eventual 1–4 loss.

[72][73] On 27 October, during the match against Bologna, Handanović made a crucial save by stopping a Mattia Destro shot in 94th minute to help Inter win 1–0 away at the Stadio Renato Dall'Ara.

[90] He captained Inter for the first time on 19 February of the following year in his 193rd appearance, taking the armband following Rodrigo Palacio's substitution and keeping a clean sheet in the 1–0 win over Bologna at Stadio Renato Dall'Ara.

[92] Eight days later, he was named Man of the Match after an impressive performance at Juventus, helping Inter to earn a goalless draw and to keep them undefeated after 16 Serie A weeks.

[101] On 13 February 2019, Inter announced via their official Twitter account that Handanović has been named new team captain, replacing Mauro Icardi.

[102] On 7 March, in the 0–0 draw against Eintracht Frankfurt in the first leg of 2018–19 UEFA Europa League round of 16, Handanović kept his 100th clean sheet on his 281st official appearance for the Nerazzurri.

[105] In the final match of the championship, he played a vital role in Inter's 2–1 home win over Empoli, making two decisive stoppage-time saves to deny the visitors the equaliser.

Handanović began his first full season as Inter captain on 26 August 2019 by keeping a clean sheet in the 4–0 home win over newly promoted side Lecce; by doing so, he achieved his 200th Serie A victory.

[119] His first UEFA Champions League clean-sheet of his career came on 23 October, in a 2–0 home win over German side Borussia Dortmund, in the third group match of the competition.

[7] He made his 500th Serie A appearance on 14 February 2021, in a 3–1 home win over Lazio, which allowed Inter to climb to the top of the league table; he became only the 15th player ever to achieve this milestone.

[127] Later on, he made his 400th appearance for the club in all competitions in a 3–1 home win over Sheriff Tiraspol in the Champions League group stage, becoming the only goalkeeper to do so.

[128] On 12 January 2022, Handanović won his second career trophy, the Supercoppa Italiana, as Inter defeated Juventus 2–1 at San Siro thanks to a 120th-minute winner by Alexis Sánchez.

[132][133] On 23 April 2023, in a 3–0 away win over Empoli, Handanović made his 563rd Serie A appearance, tying with Pietro Vierchowod as the seventh most capped player in the competition.

[140] On 26 May 2008, Handanović captained Slovenia for the first time in his 23rd cap during the friendly match against Sweden,[141] which won the game at Gamla Ullevi thanks to a Tobias Linderoth goal.

[143] Handanović then played in the remaining eight matches, keeping his goal intact in three of them as Slovenia ended the qualifying campaign in the penultimate place with eleven points.

In the team's opening match against Algeria, Handanović debuted for the first time in a major tournament, keeping a clean sheet as Slovenia managed to win 1–0 at Peter Mokaba Stadium to grab their first three points.

[149] Slovenia were eliminated from the tournament after finishing third in their group with four points, behind the United States and England, following a 1–0 defeat to the latter in their final match at Nelson Mandela Bay Stadium on 23 June.

[150] On 18 November 2015, Handanović announced his retirement from the national team after Slovenia failed to qualify for UEFA Euro 2016, crashing out with a 3–1 aggregate defeat to Ukraine in the play-offs.

[155][157][162][166][167][168][169][170][171][172] With 26 saves, he holds the record for most penalties stopped in Serie A, ahead of Gianluca Pagliuca,[6][155][173][174] although Handanović has a superior success rate.