The big-serving Australian has been in career-best form over the last few weeks but was unable to contain an inspired Frances Tiafoe on Sunday and earn a place in his first Grand Slam quarter-final.
"It definitely does feel like a little opportunity lost," he told reporters after his 6-4, 7-6(3), 2-6, 6-3 loss.
"I think this match it was changed by I think one, two, or three points. I think he won three more points than I did all match, and he won three sets. That just shows you how close it was."
Popyrin landed his first Masters title on the back of a string of upsets at the Canadian Open in Montreal last month to reach a career-high ranking of world number 23.
Given that and his stunning defeat of Djokovic, Popyrin was not about to get too upset by exiting the U.S. Open in a hard-fought contest in the last 16.
"I'm telling everybody now, if you would have told me at the start of the summer I would have been 23 in the world with a Masters title and second week of a slam for the first time, I probably would have taken it considering the position I was in," he added.
"If I hadn't won a match in Montreal or (Cincinnati), I probably would have dropped to outside 90 in the world. So considering all that, I think it was a very successful summer."
While Tiafoe will move on to try to end his country's long wait for a homegrown U.S. Open men's singles champion, Popyrin's success will have his compatriots thinking they might have a contender to do the same at the Australian Open.
With Nick Kyrgios showing no signs of an imminent return to the court, Australia is desperate for credible candidates to end a 48-year drought since Mark Edmondson triumphed in 1976.
"I haven't even thought about that yet," Popyrin said with a laugh.
"We've got Davis Cup, Asian swing, indoor swing. We still have a lot of tennis left to play this year. I'm going to take some time off I think now. I'm quite knackered."