Fourth seed De Minaur defeated Nadal 7-5, 6-6 in a battle that lasted one hour and 51 minutes to reach the third round.
The 22-time Grand Slam champion subsequently did not make scheduled appearances at the BNP Paribas Open and the Rolex Monte-Carlo Masters, Masters 1000 tournaments he had previously won three times and 11 times respectively.
Nadal was playing his second tournament of the year and his first since January when he made the quarter-finals of the ATP 250 in Brisbane.
Earlier on Tuesday, the 37-year-old was playing his first clay-court match since winning his 14th Roland Garros trophy in 2022 and recorded his 475th win on the surface.
The 22-time Grand Slam champion subsequently did not make scheduled appearances at the BNP Paribas Open and the Rolex Monte-Carlo Masters, Masters 1000 tournaments he had previously won three times and 11 times respectively.
Nadal was playing his second tournament of the year and his first since January when he made the quarter-finals of the ATP 250 in Brisbane.
Earlier on Tuesday, the 37-year-old was playing his first clay-court match since winning his 14th Roland Garros trophy in 2022 and recorded his 475th win on the surface.
