MELBOURNE, Australia — American men had an awfully good start at the Australian Open. They won seven of 10 matches, placing the most male players from the United States in the second round of the tournament since 2017.

Then things got real in a hurry.

Only Mackenzie McDonald, 25, a former N.C.A.A. champion out of U.C.L.A. who is battling his way back from hamstring tendon surgery, and Taylor Fritz, a big-serving Californian who is 23 and still evolving, survived to Round 3. By late Saturday afternoon, only McDonald remained.

The names of the two men responsible for a lot of the American carnage are familiar: Novak Djokovic and Rafael Nadal. In the span of roughly 55 hours from Wednesday afternoon through Friday night, Djokovic and Nadal dispatched Francis Tiafoe, Michael Mmoh and Fritz.

Those wins continued what has become more than a decade of mostly frustrating efforts for American men going up against the game’s so-called Big Three — Djokovic, Nadal and Roger Federer — especially in the Grand Slam tournaments.

According to Greg Sharko of the ATP, the master of match records for men’s tennis, the last American to beat Djokovic at a Grand Slam event was Sam Querrey, who bested him in the third round of Wimbledon in 2016. Since then, Djokovic has won 16 straight matches against American men at all tournaments.

Nadal’s win over Mmoh was his 10th straight over an American. The last American to beat Nadal was John Isner, the 6-foot-10 serving machine, at the 2017 Laver Cup. Earlier that year, Querrey beat Nadal at a tournament in Acapulco, Mexico. At the time, Nadal had won 16 consecutive matches over Americans, dating to the summer of 2011.

Federer has not lost to an American in a Grand Slam tournament in the past 15 years. Andre Agassi beat Federer at the 2001 United States Open, when Federer was 20.

There is, of course, little shame in struggling against Djokovic, Nadal and Federer, who skipped the Australian Open to recover from knee surgery. They are the best of the game’s modern era, the winners of 57 Grand Slam singles championships. For years, they mostly lost to one another in the biggest events.

But the failure of an American man to register the kind of signature win that can imbue a fledgling career with invaluable confidence is emblematic of the larger struggle. A country that once dominated the sport has struggled for years to find a successor to Andy Roddick, the last American man to win a Grand Slam tournament, at the 2003 U.S. Open, even as American women continue to thrive.

Isner, 35, is the lone American in the top 30. In the 1990s, just as tennis was becoming a truly global sport, Pete Sampras, Andre Agassi and Jim Courier were mainstays of the top 10. Canada, which is about one-tenth of the size of the United States, has three men in the top 20. Also, the Australian Open takes place on a hardcourt, the surface that most Americans grow up playing on.

“I think I’m more than capable, but it’s a matter of not what I do against Novak but what do you do every day,” Tiafoe, 23, said after he had lost his hard-fought four-set, three-and-a-half-hour battle with Djokovic. “Those matches, losing matches, I don’t think I should.”

Fritz came a step closer to beating Djokovic on Friday night, pushing him to five sets as Djokovic struggled through an injury he described as a torn muscle on the right side of his midsection. Fritz appeared to have Djokovic beaten early in the fifth set but fell short as Djokovic began pounding serves and ripping forehands into the corners, as he had early on in the match.

An hour after it ended, Fritz remained distraught over too many missed first serves and errors off his forehand. He had taken Djokovic to a tiebreaker in the first set and had then lost seven of the next eight points.

“It’s very motivating that we’re so close, but at the same time, we are so far,” Fritz said. “These guys are so good.”

And so it was that McDonald, perhaps the most unlikely of all of his countrymen, became the last hope to put an American into the second week of the year’s first Grand Slam. McDonald showed promise three years ago when, not long after leaving U.C.L.A., he made it to the fourth round of Wimbledon, where he lost to Milos Raonic of Canada.

Less than a year later, he sustained a torn hamstring tendon while playing doubles at the French Open and underwent surgery. After the operation, he couldn’t leave his apartment for three weeks, and he couldn’t walk for the better part of two months. Slowly, week by week, he began to allow his leg to bear more weight.

During the last two years, he has clawed his way back, training at the United States Tennis Association complex in Orlando, Fla., and playing a mix of lower-, middle- and top-tier tournaments. He was No. 192 in the world rankings entering the Australian Open, where he has played nearly flawless tennis and has also been blessed by a friendly draw.

His highest-seeded opponent, Borna Coric of Croatia, was the No. 22 seed. After beating Coric in four sets in the second round, McDonald faced Lloyd Harris, 23, of South Africa, who was playing in the third round of a Grand Slam for the first time and is ranked No. 91. It was close early, as McDonald won the first set in a tiebreaker, but not after that. McDonald cranked 12 aces and punished Harris with deep, hard backhands all afternoon.

In the fourth round, he gets Daniil Medvedev, the crafty and powerful Russian who is searching for his first Grand Slam title. With Djokovic ailing and Nadal battling a balky but improving lower back, many experts consider Medvedev a favorite to win this tournament.

After his win over Harris, McDonald insisted that American players had the raw material to challenge the greats, and everyone else who reaches the later rounds of a Grand Slam event.

“The talent is there,” McDonald said. “We just have to stay focused and keep working hard.”