The third seed from Spain overpowered the Russian to win 6-2 6-1 in a paltry one hour and 10 minutes on the Philippe Chatrier Court.
Sharapova struggled with her serve throughout the contest and made 27 unforced errors, to just 10 winners, as Muguruza dominated from the baseline.
Muguruza finds form in Paris
Muguruza arrived in Paris low on confidence after early defeats in Stuttgart, Madrid and Rome on the regular WTA Tour.
Yet, the 2016 champion has rediscovered her form on the Parisian clay, after coming through a tricky first-round test against former champion Svetlana Kuznetsova, before dismantling 2010 runner-up Sam Stosur for the loss of two games.
Mugaruza then spent just 20 minutes on court in her fourth-round match against Lesia Tsurenko, after the Ukrainian player retired with an injury early in the first set.
Sharapova had also been given a helping hand following Serena Williams' withdrawal on Monday.
Sharapova struggles on serve
If anything, though, the three-day rest appeared to disrupt the Russian, who swept past world number six Karolína Plíšková 6-2 6-1 in the third round.
Sharapova served three double faults in the opening game of the match before conceding her serve, and her opponent quickly seized the initiative.
The Spaniard hadn't beaten Sharapova in the pair's three previous tour matches, however the most recent meeting was almost four years ago.
Sharapova continued to struggle with her serve, and a fourth double fault handed Muguruza another break point in the third game, which she duly converted for 3-0.
Spaniard powers through
In contrast, Muguruza landed her first serve 66 per cent of the time in the opening set and backed it up with an array of potent ground strokes.
Sharapova, so often the aggressor from the baseline, simply couldn't live with the Spaniard's relentless power.
In truth, Sharapova did well to stretch a one-sided first set to the 45 minute mark.
The Russian did retrieve an early break after losing her serve again in the opening game of the second set.
However, her resistance didn't last long as Muguruza retook control with a couple of forceful returns, hit from well inside the baseline
In a desperate attempt to recover the situation, Sharapova made more and more errors, particularly off her forehand wing.
The Russian lost the last five games and must now turn her attentions to the upcoming grass-court season.