Inter Milan commenced the 2015–16 season with a 1–0 home win against Atalanta, where Handanović kept his first clean-sheet of the season. 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. The loss ended Inter's undefeated streak of the 2015–16 season. After the match, Handanović told the reporters that it was his fault for the way the match ended.