|US Open 2019|
|Venue: Flushing Meadows, New York Dates: 26 Aug – 8 Sep|
|Coverage: Live text and radio commentary on selected matches on the BBC Sport website and app|
Rublev, 21, ranked 35 places behind the Greek at 43rd, won 6-4 6-7 (5-7) 7-6 (9-7) 7-5 after Tsitsipas was hampered by cramping.
Tsitsipas, 21, tipped as a future Grand Slam champion, has now made first-round exits in the past two majors.
“We played an amazing match,” said Rublev, who stunned Roger Federer in Cincinnati in 62 minutes this month.
“It was tough conditions for both of us. He started to cramp. I know what it’s like; I was cramping too and tried not to show it. But this is amazing, winning matches like this gives you confidence.”
Rublev, who sealed victory in three hours and 56 minutes, will face the winner of the match between France’s Gilles Simon and American Bjorn Fratangelo in the second round.
Meanwhile, Wimbledon semi-finalist and 10th seed Roberto Bautista Agut was knocked out with a 3-6 6-1 6-4 3-6 6-3 defeat by Mikhail Kukushkin.
Elsewhere, Croatian 2014 champion Marin Cilic, seeded 23rd, beat Slovak Martin Klizan 6-3 6-2 7-6 (8-6) and Italian 24th seed Matteo Berrettini defeated Frenchman Richard Gasquet 6-4 6-3 2-6 6-2.