Cilic used his title in Flushing Meadows and runner-up finishes at Wimbledon in 2017 and the Australian Open in 2018 to reach as high as No. 3 in the ranking. But the Croatian has fallen to No. 121 this week after playing in just two matches - none in Grand Slam tournaments - this year.
Shapovalov hasn't played since a fourth-round loss at Wimbledon to Roman Safiullin on July 9. He had reached the semifinals there two years earlier for his best Grand Slam result.
The Canadian wrote in a social media post Wednesday that he had done everything possible to be healthy for the Aug. 28 start of play but that his knee needed more time.
"That grand slam energy, especially in NYC, is unlike anything else and I'm really going to miss playing in front of the amazing fans there this year!" he added, along with an emoji of a broken heart.
Shapovalov's best U.S. Open finish was the quarterfinals in 2020. He is currently ranked 22nd after reaching as high as No. 10.
Soonwoo Kwon of South Korea and Attila Balazs of Hungary moved into the main draw.