In the women's draw, reigning US Open champion Sloane Stephens kept alive her bid for back-to-back titles in NY by defeating former world number one Victoria Azarenka 6-3, 6-4 in a gritty match to set up a fourth-round showdown with Elise Mertens.
The American thrilled the NY crowd previous year by defeating compatriot Madison Keys 6-3 6-0 to claim an unexpected maiden major success - when ranked 83rd in the world and after a few months back following an 11-month foot injury lay-off.
The match lasted 4 hours, 23 minutes.
Nadal was pushed to play his best tennis Friday by the 22-year-old from Moscow, and he responded.
The third-seeded American was the sharper of the pair at the outset, firing nine winners and fending off Azarenka's lone break-point opportunity to take the first set in a little over half an hour.More news: Chip Kelly picks Michigan transfer Wilton Speight as UCLA's starting QB
Nadal, seeking an 18th major, will face Georgia's world number 37 Nikoloz Basilashvili for a place in the quarter-finals.
Stephens produced a masterclass in serving during the first set - missing only one first serve out of 20 - while strong groundstrokes helped her to bring up a triple set point at 0-40 on Azarenka's serve, which was duly won. He's young. He has everything.
"I mean, of course it was a change of momentum".
"I played her last week in Cincy", said Stephens, who fell to the Belgian in the third round in Cincinnati.
"I competed. When things got tough, I just hung in there, battled as hard as I could, ran down every ball", said Stephens, who wasn't surprised to see Azarenka raise her game in the second set.
Stephens went from up a set and a break at 3-1 in the second to down 4-3 when Azarenka took three games in a row. Nadal broke for 5-all and, after the delay, broke again to even it at a set apiece, aided by two double-faults from Khachanov.More news: US Open third round preview: Sloane Stephens vs Victoria Azarenka
"Just kind of refocusing", she said. But Khachanov put a forehand in the net there, and after a thrilling point that featured a drop shot, a lob, a leaping tweener by Khachanov and a volley victor by Nadal, they headed to another tiebreaker.
"Okay, the other two matches, we had best-of-three".
He then had to save a set point in the 12th game before cruising through the tiebreaker to claim his 25th win against just one loss since mid-May. "I'm going to give it another go".
"At this stage, it's a matter of one, two points, and today I just need to cut down my unforced errors", Azarenka told reporters. Big respect to Rafa. That's why he's No. 1 in the world, such a great fighter.
As Nadal and Khachanov clashed on Arthur Ashe, Wimbledon runner-up Kevin Anderson was battling Canada's Denis Shapovalov on Louis Armstrong Stadium. "Constant noise going on the whole time", said Anderson after his second five-setter in three rounds.More news: Washington elite among thousands honouring McCain, United States News & Top Stories