Before moving to Italy, Handanović played in his home country of Slovenia. In 2004, he was acquired by Udinese, but spent the next few years on loan, playing for teams such as Treviso, Lazio and Rimini. Handanović returned to Udinese ahead of 2007–08 season, where he played as a starter for the next five years. In the next season, he also played European football for the first time, making his debut in then UEFA Cup. After five years as starter and more than 200 appearances, Handanović joined Inter Milan in July 2012 for around €19.4m. In February 2019, he was named club captain, while in September, he made his 300th appearance for the club, and subsequently went on to reach the 2020 UEFA Europa League Final that season. He made his 500th Serie A appearance in February 2021, and won his first trophy that May by winning the title.