The Big Four in men's tennis are down to a Big Three for this U.S. Open, but are still looking to extend their dominance over the rest of the field.

Five-time champion Roger Federer is sidelined for the rest of 2016 with a knee ailment, but Novak Djokovic, Andy Murray and Rafael Nadal remain the three favorites to win the title on Sept. 11.

The Big Four have won 42 of the past 46 Grand Slam titles dating to the 2005 French Open. During that stretch, Nadal has won 14 titles, Federer 13, Djokovic 12 and Murray three. Still, two of the four exceptions during that span have happened in Queens, with Juan Martin Del Potro capturing the 2009 U.S. Open by beating both Nadal and Federer en route to the title and Marin Cilic winning the 2014 Open by crushing Federer in the semifinals.

"The Big Four are getting older," the 30-year-old Nadal said with a smile last week. "Is normal that there is new generation that tries to be in that positions, no?

"But still Novak is No. 1, Andy No. 2, and he's in good position in the race. I get injured, is true. But before the injury I was the third in the race and not very far from No. 2. Roger, is true, having is tough year in terms of injuries, too."

No. 1 Djokovic and No. 4 Nadal both won their first-round matches on Monday and are drawn to meet one another in the semifinals, yet both are battling left wrist injuries that could keep them from playing their best, especially across the two-week grind of a Grand Slam event. (Djokovic is right-handed, while Nadal is a lefty.)

No. 2 Murray was slated to play his opening match Tuesday night under the lights in Arthur Ashe Stadium.

Wearing tape on his left wrist, Nadal breezed past Denis Istomin during the day session on Ashe, 6-1, 6-4, 6-2, while during the night session Djokovic appeared to struggle with a left wrist and right arm injury in a laborious four-set win over Jerzy Janowicz, 6-3, 5-7, 6-2, 6-1.

Djokovic said he injured the wrist before the start of the Rio Olympics, where he was stunned in the first round by a resurgent del Potro, who went on to lose the gold medal match to Murray. Djokovic then pulled out of the event in Cincinnati because of the wrist. Meantime, the trainer attended to the Serb's arm during the Janowicz match.

"To be honest, I take it day by day," said Djokovic, who is seeking to win his 13th career major, one shy of Nadal and Pete Sampras' 14 and four behind Federer's all-time mark of 17. "That's what I feel at the moment. It's good, as I said, just to finish the match. I'm pleased that as the match progressed I was feeling better and better.

"Tomorrow is a new day. I hope that I'll feel overall good so I'm able to perform at my best for the next match."

Nadal, meantime, has been bothered by the wrist since withdrawing before the third round at the French Open, a tournament he has won nine times. He didn't play again until the Olympics, where he lost the bronze medal match to Kei Nishikori.

"Is not easy to go two months-and-a-half out of competition in the middle of the season without hitting a forehand," he said. "I need to have the confidence again with my wrist. That is coming, because I feel the wrist much better, and every day feel that the wrist a little bit better. That's very important thing for me. By the way, the most important thing.

"I need to recover the normal movement with the forehand. Even if I played very well in Rio, you know, when you have pain you try to change the movement to avoid a little bit that pain, no? So I need to find again the normal movement. But I am in the way."

Depending on how they feel across this fortnight, the injuries to Nadal and Djokovic could open the way for Murray to continue his brilliant late-season run. He won both Wimbledon and Olympic gold for a second time each, but did not have to play Djokovic in either event.

"To be honest, they're both in the top half," Murray said of Djokovic and Nadal. "With them having wrist problems doesn't affect my chances of getting to the final. I wouldn't have to play them in that stage, anyway."

While the Big Four have dominated, a group of other players still has the chance to break through and do damage here. No. 5 Milos Raonic, the Wimbledon runner-up to Murray; No. 6 Nishikori, the 2014 U.S. Open runner-up to Cilic; and No. 7 Cilic, who could meet Djokovic in the quarterfinals, are all potential champions.

"I mean, still the draw is 128," Djokovic said. "You still have guys like Andy, Rafa, Cilic, Nishikori, Raonic. You still have the best players in the world …

"So I think even without [Federer], it's a very strong field. I'm sure it's going to be a good tournament."

Follow Adam Zagoria on Twitter @AdamZagoria for updates throughout the U.S. Open.