In the longest match of the tournament’s first day, it took the French Open finalist nearly five hours to defeat three-time Grand Slam winner Murray 2-6, 7-6, 3-6, 6-3, 6-4 at Flushing Meadows.

Tsitsipas’ eight-minute toilet break before the deciding set angered Murray, who could be heard claiming his opponent was "cheating" with his lengthy toilet breaks after losing his serve in the second game of the fifth set, and said afterwards: "I lost respect for him."

Second seed Daniil Medvedev of Russia eased through to the second round with a 6-4, 6-3, 6-1 victory against France’s Richard Gasquet, while his compatriot Andrey Rublev beat Croatia’s Ivo Karlović in straight sets despite struggling to contain the Croatian's service game.

Karlović smashed 19 aces past the Russian but also committed three double faults as he was lost on the first day of men's singles first round matches.

The tournament's fifth seed was no slouch from the baseline himself as he hit eight aces and won an impressive 85 per cent of points on his first serve.

Despite owning a sensational first serve, Karlović struggled on his second as he won just 52 per cent of points compared to Rublev's 72 per cent.

The Croatian also failed to break his opponent despite having four break points in hand throughout the match as the Russian took two from two.

Wimbledon quarter finalist Félix Auger-Aliassime scraped through a gruelling test against Russia's Evgeny Donskoy to advance.

The Canadian was forced to a tiebreaker in three out of the four sets played but held his nerve to triumph in all of them as he won the match 7-6, 3-6, 7-6, 7-6.

The 12th seed has multiple areas of his game to improve on as he committed seven double faults and only managed one of a possible five break points.

Norway's first player to win an Association of Tennis Professionals title, Casper Ruud, comfortably beat Japan's Yuichi Sugita 6-3, 6-2, 6-2.

The eighth seed contained his opponent to just 41 per cent of points won on the second serve and also defended his serve brilliantly, not giving up a single game.

Big-serving American John Isner was shocked in straight sets by his compatriot Brandon Nakashima as the latter was the one who dominated from the baseline.

Nakashima won 7-6, 7-6, 6-3 as he took 91 per cent of points won on his first serve.

Number 23 seed Frenchman Ugo Humbert was upset by the unseeded Peter Gojowczyk.

The German defeated his opponent 1-6, 6-1, 6-2, 5-7, 6-4.

Humbert will be kicking himself for not being able to put Gojowczyk to the sword, especially considering he only converted four of 14 break points.

Argentina's Diego Schwartzman breezed past Lithuania's Ričardas Berankis 7-5, 6-3, 6-3.

Once again, however, it was far from a perfect performance as the 11th seed conceded six double faults and only landed 62 per cent of his first serves in the court.

Bulgaria’s Grigor Dimitrov, a semi-finalist in this tournament two years ago and the 15th seed, cruised past American wildcard Sam Riffice, triumphing 6-1, 7-6, 6-3.

Britain's Dan Evans also progressed in four sets with the 24th seed beating Brazil's Thiago Monteiro 6-3, 6-7, 6-4, 6-1, in a well-rounded performance.

Evans’ compatriot Cameron Norrie, seeded 26th, had a more disappointing day as he lost in straight sets to Spain’s Carlos Alcaraz.

Croatia's Marin Čilić was forced to retire with an injury in the fifth set against Philipp Kohlschreiber of Germany as the number 30 seed and former US Open winner gave his opponent victory.

The top half of the draw in the first round, with world number one Novak Djokovic of Serbia beginning his bid to become the first man since 1969 to win a calendar Grand Slam against Denmark's Holger Rune is due to start tomorrow.

Olympic champion and fourth seed Alexander Zverev of Germany is also in action action against America's Sam Querrey, and Wimbledon finalist Matteo Berrettini of Italy faces France's Jérémy Chardy.