Novak Djokovic’s US Open campaign ended in stunning fashion on Sunday after the 39-year-old suffered his earliest Grand Slam exit in more than two decades.The 24-time major champion was beaten by Argentina’s Mariano Navone 6-7 (5), 7-5, 6-4, 2-6, 1-6 in a gruelling first-round encounter that lasted four hours and 35 minutes.Djokovic struggled physically for much of the match and appeared increasingly distressed as the contest progressed. He was seen vomiting courtside several times and, during the closing stages, appeared to be in considerable pain.According to BBC reporting, Navone took advantage of Djokovic’s declining physical condition to produce the biggest win of his career.Djokovic’s physical problems overshadow five-set battleDjokovic made a promising start and moved ahead 4-1 in the opening set, but his condition soon became a major concern.He began showing signs of discomfort and was seen being sick beside the court. Despite those problems, the Serbian managed to push the first set to a tiebreak before Navone eventually edged it.The match then appeared to swing back Djokovic’s way.He recovered to take the second set and followed it by winning the third, putting himself in a commanding position. When Djokovic broke early in the fourth set to move 2-1 ahead, another comeback looked possible.Instead, his physical struggles became increasingly severe.Djokovic appeared to have difficulty breathing and was repeatedly bending over between points. His movement deteriorated and his ability to generate power on serve also suffered.BBC reported that Djokovic took a medical timeout before the deciding set because of a back problem.Mariano Navone stays composed under pressureNavone entered the contest without ever having won a five-set match, but the 25-year-old Argentine showed remarkable composure against one of tennis’ greatest players.Rather than allowing Djokovic’s reputation to dictate the match, Navone maintained long rallies and repeatedly made his opponent play another shot.His defensive work proved particularly effective. Djokovic struggled to hit through him consistently, while Navone kept retrieving balls and forcing errors and additional exchanges.He also handled the pressure when Djokovic attempted one final push in the fifth set.After falling behind, Djokovic managed to reduce the deficit to 3-1, briefly raising the possibility of another extraordinary comeback. Navone responded immediately, regained control and moved to within touching distance of victory.He then completed the upset to reach the second round.A painful night for DjokovicDjokovic admitted afterwards that the match had been extremely difficult from a physical standpoint.Speaking about his experience on court, he described the overall feeling as deeply unpleasant and acknowledged how difficult it had been to compete while struggling physically.The defeat ends a remarkable streak for Djokovic. His previous first-round loss at a Grand Slam came at the 2006 Australian Open, meaning he had gone roughly two decades without being eliminated at a major at the first hurdle.The result is particularly surprising given his record at the US Open and his ability to remain competitive deep into major tournaments even at the later stage of his career.Djokovic arrived in New York short of preparationThe Serbian entered this year's tournament without the usual volume of competitive tennis behind him.He had played only one match since reaching the Wimbledon semi-finals and was defeated in the opening round of the Cincinnati tournament.After that loss, Djokovic had spoken about a health problem that could become more troublesome in humid conditions, adding another layer of uncertainty ahead of the US Open.His lack of match practice appeared noticeable against Navone, particularly once the physical issues intensified.Despite the setback, Djokovic’s recent Grand Slam record shows that he remains capable of challenging the leading players. He reached the Australian Open final earlier this year and also made the Wimbledon semi-finals.What the result means for Djokovic’s Grand Slam hopesDjokovic’s immediate future in Grand Slam tennis is now likely to attract plenty of attention.He has continued to compete at the highest level despite being 39, and he has previously spoken about his ambition to compete at the 2028 Olympic Games in Los Angeles.For now, however, the defeat represents another setback in his pursuit of a record-extending 25th Grand Slam singles title.The opportunity to add another major trophy has become increasingly difficult as younger players continue to challenge the established order.Sunday’s loss does not erase Djokovic’s extraordinary achievements, but it underlines the physical demands facing a player at this stage of his career.US Open draw opens up after Djokovic exitDjokovic’s elimination also has major consequences for the tournament itself.For the first time since 2003, a Grand Slam will reach its second round without Djokovic, Rafael Nadal or Roger Federer. With Nadal and Federer retired and Djokovic now out, a remarkable era of men's tennis has become even more distant.The result could also dramatically alter the complexion of the US Open draw.Jannik Sinner is already out, while Carlos Alcaraz has returned to competition after a four-month absence caused by a wrist injury. Djokovic’s departure therefore creates an unexpected opportunity for players in the lower half of the draw.American hopes could receive a particular boost. Frances Tiafoe and Brandon Nakashima are among those who could benefit from the opening, while former US Open champion Daniil Medvedev will also see a clearer route through the section.The possibility of an American men's singles champion has consequently become a major talking point. Andy Roddick remains the last American man to win the US Open, having lifted the trophy in 2003.With Djokovic gone at the first hurdle, the tournament has suddenly lost one of its biggest names — and created an opportunity for a new champion to emerge.