The Spaniard suffered the earliest exit by a defending Ladies' champion at the All-England Club since 1994 when Steffi Graf was knocked out in the first round by Lori McNeil.
The 47th-ranked Van Uytvanck, who captured a title earlier this year in Budapest, recorded her first career Top 10 win and advances to a third-round matchup with 28th seed Anett Kontaveit.
Muguruza takes tight opening set
It was Muguruza who had the first break chance in the opening game of the match, but a backhand dumped into the net erased that opportunity and Van Uytvanck would go on to record a hold.
The next four games went with little incident as the server was in full control, the Belgian taking a 3-2 lead. She would earn a break point when the Spaniard slapped a forehand long and take it with a forehand winner of her own.
Three of the next four games would be breaks, including Muguruza failing to serve out the set at 5-4. She would earn two more break points in the eleventh game, the first bypassed on a forehand just long, but converting on the second when Van Uytvanck missed a backhand.
With a second chance to serve out the set, the defending champion was quick to build a 40-0 lead and a forehand that just clipped the baseline put the third seed in front after 48 minutes of play.
Van Uytvanck evens the match
The players traded breaks to begin the second set and Muguruza was nearly on the front foot again in the third game, getting to deuce before some big hitting got Van Uytvanck out of trouble.
The sixth game proved to be the turning point of the match, Muguruza was broken as Van Uytvanck took her third chance, blasting a forehand winner for a 4-2 lead.
After saving a break point to hold for a 5-2, the world number 47 was soon level in the match, a drop shot forcing Muguruza to hit into the net on set point.
Belgian runs away with final set to complete shocker
The third set began with the server winning 12 straight points as Van Uytvanck held a 2-1 lead. The fourth game would last 13 points with the Belgian holding two break points.
On her first chance, Van Uytvanck nervously hit a backhand into the net, but given a second opportunity, it was the Spaniard who fired a backhand into the net to give the Belgian a 3-1 lead.
After a hold to 30, Van Uytvanck would break one last time for a 5-1 lead.
Serving for the massive upset, the Belgian fell behind 0-30, but got to match point at 40-30 and with one last Muguruza forehand into the net, the stunner was complete.