In the 2009–10 season, under manager Leonardo, Inzaghi was relegated to the role of backup player with his contract set to expire in June 2010. On 21 May 2010, he was offered a new one-year contract which would last until 30 June 2011.
On 3 November 2010, in the UEFA Champions League 2010–11 Group Stage campaign, with Milan trailing by 1–0 to Real Madrid, Inzaghi came off the bench in the second half and scored a brace to give Milan a 2–1 lead. Pedro León, however, equalized in the 94th minute, with the final score ending 2–2. On that occasion, he became the new all-time top scorer of all European club competitions with 70 goals. He also became the second-oldest player to score in the Champions League, aged 37 years and 85 days, behind only Manchester United's Ryan Giggs, now surpassed by Inzaghi's compatriot Francesco Totti. With these two goals, Inzaghi went ahead of his idol Marco van Basten on the club list of the all-time top goalscorers with 125 goals.
On 10 November 2010, Inzaghi suffered a serious injury while playing for Milan against Palermo. A statement on the official Milan club website confirmed that Inzaghi had suffered a lesion of the anterior cruciate ligament (ACL) and associated lesion to the external meniscus of the left knee. It was thought he would be out for the rest of the season. Due to his age, this injury could have ended his career; nonetheless, Inzaghi was very optimistic. On 7 May 2011, with Inzaghi still out recovering from his injury, Milan won the 2010–11 Serie A title. After being sidelined by injury for six months, he came off the bench for the first time since his injury on 14 May, with Milan defeating Cagliari 4–1. He extended his contract till June 2012 during the 2011–12 pre-season.