Muguruza came from a break down to survive a nervy first set but there was no let off in the next two and the third seed was left shaking her head in disbelief as van Uytvanck bombarded her with serves that often clocked at over 110mph, with the fastest recorded at 115 miles per hour.
He faces Alex de Minaur next.
"I was just not feeling as comfortable as yesterday with hitting", he said. But I didn't panic.
But considering that as of Wednesday, five of the top-10 seeds in the women's draw were spending the remainder of the fortnight preparing for the hard-court season, no match at Wimbledon, no matter the round nor tale of the tape, is a foregone conclusion. Muguruza, meanwhile, owns two major titles, including the 2016 French Open, and was the runner-up at the All England Club in 2015. I should have won my serve, I have to really work on much, much more.
"I'm appreciating fully how I am working now, how I'm competing now, trying to build on this now".More news: 'It's Coming Home!' England fans get World Cup fever
Ostapenko, victor of the 2017 French Open title, saw off Yulia Putintseva 6-2 6-3, while Daria Gavrilova got past fellow Australian Sam Stosur 6-4 6-1.
Muguruza was broken seven times by the inspired 47th-ranked Belgian, ending the Spaniard's hopes of retaining her title.
Fourth seed Alexander Zverev was teetering on the brink of defeat when he trailed Taylor Fritz of the United States by two sets to one when their second round tie was suspended for the night.
"I don't know how [I've pulled those wins off] but I can say I'm a big fighter and think I can now have confidence", said Siniakova. The 24-year-old, who is also campaigning against bullying, said coming out as gay hadn't lifted a weight off her shoulders, or helped her compete better, neither was she looking to be a role model.
"When I'm done practicing I go to my house, play video games".More news: North Korea says talks with Pompeo were ‘regrettable’
Third seed Marin Cilic was stunned 3-6 1-6 6-4 7-6 (3) 7-5 by Argentina's world number 82 Guido Pella in three hours 12 minutes.
Until the final point of her 3-6, 6-2, 6-4 comeback win over Liu was recorded on Thursday, it was unclear whether Kerber would be able to stave off the unrelenting Wimbledon rookie and keep her name off a growing list of top-seed upsets. "You can not force me to change my shorts in front of everybody, you know".
South Africa's Kevin Anderson wrapped up his rain-interrupted match against Andreas Seppi on Court Two winning 6-3 6-7 (5) 6-3 6-4. "I think I was playing better than before".
Australia's Ashleigh Barty beat Canada's Eugenie Bouchard 6-4 7-5 in a match between former Wimbledon girls champions. That's why she could develop that kind of level. She would earn a break point when the Spaniard slapped a forehand long and take it with a forehand victor of her own.More news: Mother Teresa's Missionaries of Charity worker charged for 'selling' newborn