Draper looked well positioned for another big result at Flushing Meadows when he led 27th seed Karen Khachanov by a break in the third set of their third-round clash.
But he was beginning to struggle with a thigh problem that continued to get worse and, after losing four successive games to trail 6-3 4-6 6-5, Draper decided to call it a day.
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He said: “It was just the top of my hamstring, the insertion between the hamstring and the groin. I’ve had problems with it before, and maybe this time it was just a lot of tennis I’ve played in the last seven weeks just caught up a little bit on me.
“I think I did it 2-0 in the third. I went out to a wide ball and I just felt a twinge. I feel like, when you strain something and it’s getting worse, there is just no going back from that, really.
“Especially at this level, you can’t compete if you’re injured. It was a tough one.”
Draper, who will break into the top 50 at the end of the tournament, highlighted both the rapid strides he has made this season and his enormous potential by defeating sixth seed Felix Auger-Aliassime in the second round.
I think there is a lot of positives I can take from the match but I think the main thing is that I still need to improve my body.
He made a slow start against Khachanov but turned the match around well in the second set, his powerful serve and groundstrokes beginning to do some damage.
But it became clear Draper was in physical trouble when he took a medical time-out after five games of the third set and headed off court.
He won two games in a row on the resumption, with Khachanov perhaps affected by the delay, but was unable to serve out the set and pulled the plug shortly afterwards.
Draper was not too downhearted, though, saying: “I think there is a lot of positives I can take from the match but I think the main thing is that I still need to improve my body. My body is just not ready to go really deep in this tournament.
“This is my second slam on merit. It’s very different playing the five-set matches. I’ve beaten a couple of really good players, and I felt like today I was coming back. I would have had a chance to win that match if I was injury free.
“I can be very positive about the year I’ve had so far as well. When I look back, I was thinking about stopping tennis during Covid. So, to think I’m here now and I’ve broken the top 50 this week, I’m very proud of myself.”
Draper, a late physical developer, had become disenchanted by injuries and the unglamorous grind of the lower rungs of the tennis ladder, but he is now bounding towards the top of the game.
“I’ve had a lot of experiences being injured and having a lot of low moments for sure in the last few years,” he said.
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“I know the only way to do it is to keep your head up and stay positive, with your shoulders back and just keep moving forward. There’s plenty of worse things going on in the world than getting injured in the third round of the US Open when I’m 20 years old.
“I think the exciting thing is I’ve got such a long way to go, I can improve so much. My game is probably at 60 per cent of my capacity. I honestly believe that. I think I’m ready to do it, but it’s just going to take time.”
Draper expects to be fully recovered in two to three weeks but that is likely to rule him out of Britain’s Davis Cup campaign in Glasgow later this month.