But the Greek, 24, was unable to win any of the first 11 games as he lost in four sets to world number 94 Galan, who prevailed with a ninth match point.

Russian world number one Medvedev beat American Stefan Kozlov 6-2 6-4 6-0.

Medvedev, 26, claimed his first Grand Slam title in New York last year by beating Novak Djokovic, who was not allowed to travel to the United States because he is not vaccinated against Covid-19.

He will play Frenchman Arthur Rinderknech in the second round following his comfortable win on Arthur Ashe Stadium.

Colombian qualifier Galan, meanwhile, faces Australian Jordan Thompson next after securing the biggest win of his career on his main-draw debut at Flushing Meadows in New York.

Although Tsitsipas claimed a must-win third set to keep his hopes alive, Galan was able to recover from a break down in the fourth and won four of the final five games to seal a memorable 6-0 6-1 3-6 7-5 victory.

It leaves Spaniard Rafael Nadal, who is seeking a 23rd major title, his compatriot Carlos Alcaraz, and Norway's Casper Ruud - who beat Britain's Kyle Edmund in his opener - as the three players who can threaten Medvedev's position as world number one this fortnight.

Medvedev was banned from competing at Wimbledon this summer because of Russia's invasion of Ukraine, although he remained the top-ranked men's player after the grasscourt Grand Slam was stripped of its ranking points because of that decision.

Returning to action at a major - although not permitted to compete under the Russian flag - Medvedev secured victory in emphatic fashion as he closed out the match by winning eight successive games.

Elsewhere in the men's draw, Britain's 2012 winner Andy Murray beat Argentine 24th seed Francisco Cerundolo 7-5 6-3 6-3.

Another seed to fall was American 10th seed Taylor Fritz, who lost to compatriot Brandon Holt - the son of two-time US Open champion Tracy Austin - 6-7 (3-7) 7-6 (7-1) 6-3 6-4.

Spanish 16th seed Roberto Bautista Agut also suffered an early exit against American JJ Wolf, losing 6-4 6-4 6-4.

Meanwhile, Italy's 2021 Wimbledon finalist Matteo Berrettini recorded a comfortable 6-2 6-3 6-3 win over Chile's Nicolas Jarry, while Canadian sixth seed Felix Auger-Aliassime beat Switzerland's Alexander Ritschard 6-3 6-4 3-6 6-3.

This year's Wimbledon runner-up Nick Kyrgios also advanced, beating his fellow Australian - and doubles partner and best friend - Thanasi Kokkinakis 6-3 6-4 7-6 (7-4).

Austria's 2020 winner Dominic Thiem lost 7-5 6-1 5-7 6-3 to Spain's Pablo Carreno Busta as he continues to search for his best form after a lengthy lay-off with a wrist injury.

Stan Wawrinka, the 2016 winner, retired injured after losing the two opening sets of his first-round match 6-4 7-6 (9-7) to France's Corentin Moutet.

Wu Yibing became the first Chinese man to win a singles match at a Grand Slam in 63 years - since Fu Chi Mei at Wimbledon in 1959 - with his 6-3 6-4 6-0 victory over Georgia's world number 35 Nikoloz Basilashvili.

Wu, ranked 174 and who came through qualifying, is also the first Chinese man to win a US Open singles match since Guy Cheng in 1935.

The Netherlands' Tim van Rijthoven saved seven match points in the third set against China's Zhang Zhizhen before sealing an improbable comeback victory, winning 3-6 6-7 (4-7) 7-6 (11-9) 6-1 6-4.

Sebastian Korda - son of former world number two Petr Korda and and brother of golf stars Jessica and Nelly - beat Argentine qualifier Facundo Bagnis 5-7 7-6 (7-3) 7-5 6-1.