Rafael Nadal defeated the 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.

[2] This marked the fourth tournament that Nadal had won on 10 or more occasions (in addition to the French Open, the Monte-Carlo Masters, and the Barcelona Open), making him the only tennis player to do so.

(Djokovic equaled this record later that year at the US Open, while attempting to complete the Grand Slam).

[4] Lorenzo Sonego became the first Italian man to reach the semifinals in Rome since Filippo Volandri in 2007.

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