The Belgian, ranked 47th in the world, put on a brilliant performance and won 5-7, 6-2, 6-1 in the All England Club twilight.
Muguruza was strangely out of sorts and could not cope with Van Uytvanck’s tremendous hitting.
The Spaniard becomes the sixth top-ten seed to lose in the opening two rounds of this year’s tournament, but this was the biggest shock of all.
Van Uytvanck said she had no choice but to be aggressive.
“I had to play like that I think, otherwise I wouldn’t have a chance,” she insisted.
“Obviously she’s so aggressive, so if I kept letting her play I would lose anyway. So I was like, ‘Let’s try this and maybe if it works we have a chance’.
“So that was my plan to do in the second set and in the third, and obviously it worked well.”
Muguruza joins fellow top-ten seeds Caroline Wozniacki, Sloane Stephens, Elina Svitolina, Caroline Garcia and Petra Kvitova in being knocked out in the first four days. World No 1 Simona Halep made it through to the second round with a 7-5, 6-0 win over Saisai Zheng on Court One.