NEW YORK — The cramping became so debilitating, Milos Raonic said, he couldn’t grip his racket properly.

The Wimbledon runner-up just last month, and seeded No. 5 at the U.S. Open, Raonic began to feel pain near his left wrist midway through the second set of what would become a stunning 6-7 (4), 7-5, 7-5, 6-1 second-round loss to 120th-ranked American qualifier Ryan Harrison on Wednesday.

Eventually, the problem spread to Raonic’s right forearm. Then both thighs. Then his left hip. Afterward, his back seized up when he tried to sling his gear bag over a shoulder.

“It was just catching me all over,” Raonic said. “I started getting small (cramps) where I couldn’t hold the racket. I couldn’t switch grips from one point to the next.”

He was one of a trio of highly seeded players to exit Flushing Meadows on Day 3, but the other departures were less surprising.

No. 3 Garbine Muguruza, the French Open champion, made 38 unforced errors and bowed out 7-5, 6-4 against Anastasija Sevastova at night. All four of Muguruza’s U.S. Open appearances have ended in the first or second round. No. 9 Svetlana Kuznetsova, the 2004 champion, took the first four games before losing 6-4, 6-4 to Caroline Wozniacki, who is unseeded but can rely on the muscle memory from two trips to the final in New York.

In a late-night match, No. 4 Rafael Nadal of Spain defeated. Andreas Seppi of Italy, 6-0, 7-5, 6-1.

For Harrison, it finally was the sort of breakthrough victory predicted long ago for him. He entered Wednesday with a 1-26 record for his career against top-10 opponents

The 24-year-old, born in Louisiana and now based in Texas, earned his first trip to the third round at a Grand Slam tournament. He had been 0-6 in second-round matches.

Until Monday, Harrison hadn’t won a main-draw match at any major in 3 years.

Last week, Harrison and his sibling Christian, 22, became the first pair of brothers to both qualify for the U.S. Open.

“How cool,” the older Harrison said, “is it to have him with me at the Open?”

While Christian lost in the first round Tuesday, Ryan took pleasure in being joined in the third round by a couple of other Americans: No. 20 John Isner beat Steve Darcis 6-3, 6-4, 6-7 (10), 6-3, and No. 26 Jack Sock defeated Mischa Zverev 6-1, 6-1, 6-2.

Harrison next faces 44th-ranked Marcos Baghdatis, the 2006 Australian Open runner-up.

Baghdatis eliminated 32nd-seeded Benoit Paire of France 6-2, 6-4, 3-6, 6-4.

“Not really a whole lot of time for reflection in this sport, because things change so quickly,” Harrison said.