Argentine Guido Pella upset Kevin Anderson on Friday at Wimbledon, ousting the fourth-seeded South African 6-4, 6-3, 7-6 (4) in the third round.
Anderson was the 2018 runner-up at the All England Club, losing to Novak Djokovic in straight sets.
Pella countered Anderson's big serve, which reached 136 mph, by varying his shots and keeping his opponent on the run throughout a match that lasted two hours and 34 minutes.
Pella, the No. 26 seed, will play 2016 finalist Milos Raonic on Monday.
Raonic, from Canada, is the No. 15 seed and defeated Reilly Opelka in the third round on Friday 7-6 (1), 6-2, 6-1.
Pella, ranked No. 26 in the world, won the first set on a service break, one of three he converted on the day.
"He made life really difficult for me, I felt. He moves really, really well," said Anderson, who has been limited to just four tournaments this year because of a right elbow injury. "I felt I had a pretty hard time keeping him on defense, finishing out the points. When I was able to do that, I had the most success. Overall, I didn't feel like I played that bad of a match. I could have probably served a little bit better... It was very difficult at times out there."
With Anderson's loss, the fourth through seventh seeds on the men's side have been eliminated, along with Nos. 9 and 10.
No. 5 Dominic Thiem of Austria, No. 6 Alexander Zverev of Germany and No. 7 Stefanos Tsitsipas of Greece all fell earlier this week in the first round.
No. 9 seed John Isner lost Thursday in the second round.
And in another third-round loss on Friday, No. 10 Karen Khachanov of Russia was ousted by Spaniard Roberto Bautista Agut, the 23rd seed who won, 6-3, 7-6 (3), 6-1.
Among the top 10, that leaves only the top three seeds -- multiple Grand Slam winners Djokovic, Roger Federer and Rafael Nadal -- and No. 8 Kei Nishikori of Japan, who will try to avoid the upset trend in the third round on Saturday against American Steve Johnson.
Djokovic hit just a slight bump on Friday, dropping one set as he advanced to the fourth round, defeating Hubert Hurkacz of Poland 7-5, 6-7 (5), 6-1, 6-4.
With the win, Djokovic will make his 12th appearance in the Round of 16 at Wimbledon, tying Boris Becker for third place. Only Jimmy Connors and Roger Federer, each with 16 trips to the round, have made more.
"Credit to Hurkacz for playing well. He pushed me. He served well. He attacked the ball mid-court. He gave it all and played a great quality match," Djokovic told reporters. "I should have capitalized on my opportunities also in the second set. I wasn't really on top of his second serve. I was a bit hesitant in the play, which wasn't the case in the first two matches.
"But I think third set was great. Fourth set, as well, very solid. I'm really pleased with the way I finished the match."
In the fourth round, Djokovic will face upstart Frenchman Ugo Humbert, who defeated Canadian teenager Felix Auger-Aliassime 6-4, 7-5, 6-3 in two hours and nine minutes.
Humbert, 21, never had announced past the second round of a Grand Slam tournament until this week. And when he meets Djokovic on Sunday, Humbert -- the world's 66th-ranked player -- will play a top-10 opponent for the first time.
The upset bug extended to the No. 11 seed Russian Daniil Medvedev, who was dropped by No. 21 David Goffin of Belgium in three hours, 34 minutes, 4-6, 6-2, 3-6, 6-3, 7-5.
No. 28 Benoit Paire of France defeated Jiri Vesely of the Czech Republic 5-7, 7-6 (5), 6-3, 7-6 (2) while Spain's Fernando Verdasco defeated Italy's Thomas Fabbiano 6-4, 7-6 (1), 6-4.