2021 Italian Open – Men's singles

Rafael Nadal defeated defending champion Novak Djokovic in the final, 7–5, 1–6, 6–3 to win the men's singles tennis title at the 2021 Italian Open. It was his record-extending tenth Italian Open title and record-equaling 36th and last Masters 1000 title overall (matching Djokovic's tally). Nadal saved two match points en route to the title, in the third round against Denis Shapovalov. This marked the fourth tournament won by Nadal on 10 or more occasions (in addition to the French Open, the Monte-Carlo Masters, and the Barcelona Open), making him the only men’s tennis player to win more than two tournaments 10 or more times.

It was Djokovic's sixth runner-up finish at the Italian Open, a record for the most runners-up finishes at one event on the ATP Tour (Djokovic equaled this record later that year at the US Open). The final marked Djokovic and Nadal's sixth meeting in the Italian Open final (following 2009, 2011, 2012, 2014, and 2019).

Lorenzo Sonego was the first Italian man to reach the semifinals in Rome since Filippo Volandri in 2007.