The announcements came one by one, like a list of ailments from a middle-aged rec league. Balky knee. Long-term foot pain. A hamstring tear that just won’t heal. Only these belonged to three of the greatest tennis players of all time, Roger Federer, Rafael Nadal, and Serena Williams.

All three of them withdrew from the U.S. Open in the space of two weeks. And with their exits came a sobering realization for the sport: when the tournament begins on Monday, the U.S. Open will be the first Slam held without at least one of them this century. The end of an era is coming.

“We all miss them. We’d all love them to play forever,” said men’s world No. 4 Alexander Zverev. “At some point they will have to retire.”

It’s the hard truth that tennis fans have been doing their best to ignore for nearly a decade. But it’s already impossible to miss the legend-shaped holes in the men’s and women’s draws in New York. That trio alone represents more than a third of all major tournament wins since 2000. So in the grand scheme of tennis history, this could go down as the Slam that turned the page on the Roger-Rafa-Serena epoch of tennis. 

Especially if a certain Novak Djokovic does what most people expect him to and wins the whole thing. 

Not only would he complete the first men’s calendar-year Slam since Rod Laver in 1969—something neither Federer or Nadal has ever managed. He would also claim an unprecedented 21st major men’s title, taking the lead in the three-player race for history for the first time in his career. 

Should Djokovic pull it off, it’s very possible that neither Federer or Nadal will ever catch him. Djokovic is still at the height of powers. Federer, who hasn’t won a major since the 2018 Australian Open, has no horizon for returning to the game. And Nadal’s best shot of adding to his tally comes just once a year at the French Open. 

“My participation here, without Rafa and Roger participating, I feel it,” Djokovic said of his status as a prohibitive favorite in Queens. “I know there’s a lot of people who are going to be watching my matches and expecting me to do well and fight for a Slam.”

Novak Djokovic is seeking to complete the first men’s calendar-year Slam since Rod Laver in 1969.

Photo: robert deutsch/Reuters

While he trains his sights on No. 21, the people he shared the stage with for so long are asking themselves big questions not just about whether they can win anymore Slams, but about whether they can play at a high level at all. 

A decision on retirement now feels like it could come at any moment, particularly for Federer and Williams, who will both be 40 by the end of September. Both have said that they will see out their recoveries, yet neither has offered any kind of timeline. For Federer, who is undergoing a third knee surgery in the space of 18 months, even the 2022 Australian Open is likely off the table. 

Williams, meanwhile, is approaching five years since she last won a Grand Slam and 18 months since she last won a tournament of any kind. The possibility that she will one day match Margaret Court’s record of 24 majors now seems remote.

“We’ve done everything we could,” Williams’ coach Patrick Moratoglou said. “It is heartbreaking, but this is the only possible decision.”

How and when to call it quits is trickier in tennis than in most sports. The simple nature of the tennis tour means that a decline can be drawn out and painful. Injuries turn into absences and absences snowball into rankings slides, because players are no longer amassing points on the circuit. When they return, they are seeded lower and face better opponents early in tournaments. 

Williams, Nadal, and Federer have accepted that fate in recent years. They felt that it was more important to manage their appearances and pick their spots carefully, because they could no longer take the pounding of four Slams on three surfaces. But if their results have proven anything, it’s that the surgical approach, which costs them rhythm and match fitness, is no way to build a season. 

“I can understand that Roger, Rafa and Serena, myself are not that young anymore,” Djokovic said. “The new generation obviously can play probably more tournaments in a season. The bodies can sustain that effort and that beating in a way. We have to be, I guess, a little bit more selective.”

Djokovic was being generous. There is nothing selective about his calendar: he has missed just one Slam since 2005. And this season, he squeezed in the Olympic singles tournament halfway around the world in Japan, where he decided it might be a good idea to tack on the mixed doubles as well. (He left without an Olympic medal.)  

As much as his unparalleled defense and his superhuman grit, Djokovic’s place in the record books will be down to his body’s apparent unbreakability. Though he often complains of aches and pains early tournaments, he still moves at 34 as if he’s made of rubber and grinds down opponents like no one else. 

The 2020 U.S. Open was played without fans in attendance.

Photo: robert deutsch/Reuters

Djokovic’s field of would-be challengers in Flushing includes three men ranked in the world’s top five—No. 2 Daniil Medvedev, No. 3 Stefanos Tsitsipas, and No. 4 Alexander Zverev. But while they give him a run for his money at lesser tournaments on the circuit, none of them has ever beaten him in the majors’ best-of-five format. Keeping pace with Djokovic at all is hard enough. Doing it for four or five hours is near impossible. Djokovic has only lost one five-setter in the past three years. 

“I really wish for me to maybe one day be at that level of consistency and be able to dominate Grand Slams at such a level,” Tsitsipas said. “I think he has learned throughout the years how to preserve his best strengths and kind of expose them at the right moment, at the right time.”

Write to Joshua Robinson at Joshua.Robinson@wsj.com