On 12 January 2020, Zaniolo suffered an anterior cruciate ligament injury in his right knee during a 2-1 home defeat to Juventus. He started training in late June 2020. He also received messages of support from both the Italian and global football community, including Roberto Mancini, Roberto Baggio and Francesco Totti, who had previously operated on by the same surgeon.
On 5 July 2020, Zaniolo returned to the field against Napoli, where they were defeated 2-1 away in Serie A, and was included in the game at the 66th minute. A week later, Zaniolo scored his first goal after injury against Brescia in a 3-0 away win, and then his second goal against SPAL on 22 July 2020 in a 6-1 away win.
Zaniolo, who had another anterior cruciate ligament injury during the national break, closed the 2020-21 season. In July 2021, he returned to the field with the team under the management of new coach José Mourinho before the season. After his second injury, Zaniolo scored his first goal against Trabzonspor in the first match of the European Conference League.