In the final, Evans, 34, trailed 4-0 but overcame it with both mental and physical toughness to win 6-7 (6-8) 7-6 (7-2) 7-6 (7-4) 4-6 6-4.
Russian 23rd seed Khachanov saved two match points before smashing the third into the net in a nail-biting finish.
Evans smiled broadly and then fell back into his chair, weary.
Standing ovations for both players were well-deserved by the fascinated and amused spectators on a crowded outdoor court at Flushing Meadows.
Evans said to Sports, “I just tried to keep fighting because I thought I was out at 4-0.
have a severe headache right now. It was an incredible match. All I want to do is head to bed.
Jack Draper and Katie Boulter, the top-seeded Brits, advanced to the second round earlier with different winning strategies.
The 31st-seeded Boulter overcame a nervous start to defeat Belarusian qualifier Aliaksandra Sasnovich 5-7 6-2 6-1.
Shortly after, in New York, Chinese first seed Zhang Zhizhen resigned due to a knee injury, and 25th seed Draper easily defeated him, winning 6-3, 6-0, 4-0.