NEW YORK -- After double faulting to fall behind two sets to none -- a deficit he has never overcome -- in the second round of the US Open on Thursday night, Carlos Alcaraz slung his equipment bag over a shoulder and trudged toward the locker room.

Glancing in the direction of his coach, 2003 French Open champion Juan Carlos Ferrero, Alcaraz pointed his right index finger at his temple, then wagged that finger, as if to say, "I'm not thinking straight."

He might have been excused for being confused by what was transpiring under the closed retractable roof at Arthur Ashe Stadium on a chilly evening, and one set later, Alcaraz's 15-match Grand Slam unbeaten streak was over with a sloppy 6-1, 7-5, 6-4 loss to 74th-ranked Botic van de Zandschulp.

"It was a fight against myself, in my mind, during the match," Alcaraz said. "In tennis, you are playing against someone that wants the same as you -- to win the match -- and you have to be as ... calm as you can, just to think better in the match and try to do good things. Today I was playing against the opponent, and I was playing against myself, in my mind. A lot of emotions that I couldn't control."

The result eliminated the pre-tournament men's favorite and certainly was hard to predict beforehand, given the No. 3-seeded Alcaraz's standing in the game, his excellence of late and his opponent's far-lesser résumé.

It followed another exit in Ashe for a past US Open champion, Naomi Osaka, who was sent home Thursday by Karolina Muchova 6-3, 7-6 (5). That one, though, was not anywhere near what happened to Alcaraz.

He won the French Open in June and Wimbledon in July to raise his career total to four major championships, including taking the title at Flushing Meadows in 2022. Then, in early August, Alcaraz won a silver medal at the Paris Olympics, losing to Novak Djokovic in the final.

Maybe, Alcaraz acknowledged, a tennis schedule he called "so tight" drained him too much.

"Probably, I came here with not as much energy as I thought that I was going to [have]," he said. "But, I mean, I don't want to put that as excuse."

What's clear is he never found his footing against Van de Zandschulp, a 28-year-old from the Netherlands. Alcaraz was off, repeatedly missing the sorts of shots he routinely makes.

The 21-year-old from Spain came in with a 16-2 record at the US Open, where he never lost before the quarterfinals in three previous appearances. This also was Alcaraz's earliest defeat at any major tournament since bowing out in the second round of Wimbledon in 2021 as a teenager; he has never been beaten in the first round at a Slam event.

In contrast, Van de Zandschulp only once has been to a Grand Slam quarterfinal, getting that far at the US Open in 2021.

Otherwise, he is not someone most folks would have expected to pull off this sort of monumental upset. Consider: Van de Zandschulp was just 11-18 for the season at the start of this week and hadn't won consecutive matches at a tour-level event in 2024 until now.

"Actually, I am a little bit at a loss for words," he said. "It's been an incredible evening for me."

It sure was.

The key stat was that Van de Zandschulp won the point on 28 of his 35 trips to the net.

The opening set was unbelievably lopsided. With Van de Zandschulp's powerful forehands and serves at up to 132 mph finding their marks, Alcaraz never seemed to get comfortable.

He did not produce a single winner in that set and was nearly doubled up in total points, 24-13. The second set was a bit better for him, but not enough so, and a double fault gift-wrapped a service break that put Van de Zandschulp up 6-5. When Alcaraz pushed a forehand wide to end the next game, Van de Zandschulp finished off a hold at love that gave him the initial two sets after 1 hours of play.

It didn't take long for Alcaraz to fall behind by a break in the third, at 3-2, but he made a stand immediately -- with help because Van de Zandschulp's double fault ceded a break that made it 3-all. Alcaraz then held at love and smiled as he strutted to the changeover.

That grin quickly was gone, though, because Alcaraz's mistakes kept arriving, and Van de Zandschulp never folded.

"Of course I had some nerves, but I think if you want to beat one of these guys, you have to keep your calm and keep your head there," said Van de Zandschulp, who will face No. 25 seed Jack Draper of Britain in the third round Saturday. "Otherwise, they take advantage of it."

Alcaraz's is the first top-three men's seed to lose within the first two rounds at the US Open since 2006, when No. 3-seeded Ivan Ljubicic lost in the first round to Feliciano López. The second-round loss is the earliest by a men's US Open pre-tournament betting favorite since Patrick Rafter in 1999, who was defending champion but retired from his first-round match against Cedric Pioline because of a shoulder injury.

Alcaraz had entered the night 25-1 in majors against players ranked outside the top 50, with the lone loss coming against No. 95 Mikael Ymer in the second round of the 2021 Australian Open.

The Associated Press and ESPN Stats & Information contributed to this report.