The 25-year-old last played during Wimbledon in July, where he won his sixth Grand Slam, and has been missing from the tour ever since.
In a statement posted to his social media, the Italian said: "Even though I have been working hard with my team and my medical staff, we have now had to make the difficult decision that I will not be able to compete at the US Open this year.
"We have been back on court in Monte Carlo over the last couple of days and have realised that I still need more time to recover from my right knee issue. I’m obviously very sad and disappointed, as New York has a special place in my heart.
"I was very much looking forward to coming back and playing in the electric atmosphere in front of the great fans there," Sinner concluded.
The news comes just days after Carlos Alcaraz confirmed his participation at Flushing Meadows, with his fitness also in question over the last few weeks.
Draper also withdraws
Jack Draper has also withdrawn from the US Open, with the Lawn Tennis Association announcing the Briton's absence hours after Sinner pulled out of the event.
While the LTA did not disclose the nature of Draper's injury, media reports said the 24-year-old withdrew because of a long-term left arm problem.
Draper climbed to a career-high ranking of world number four in 2025 but was forced to cut short his season because of a bone injury in his arm. He has also battled a knee injury this year.
Now ranked 143rd, Draper suffered early exits in Montreal and Cincinnati.
His best Grand Slam performance came at the 2024 US Open, where he reached the semi-finals.
The US Open gets underway on Sunday, with the final on September 13th.
