The Spanish third seed, who claimed the title in 2016, dominated from the start and ended the Russian 30th seed's hopes with a 6-2 6-1 victory in 70 minutes.
The reigning Wimbledon champion, 24, has not dropped a set at Roland Garros.
She will play Romania's world number one Simona Halep or Germany's Angelique Kerber in the last four.
Both Muguruza and Halep, who is searching for her first Grand Slam title, could finish the tournament as the world number one.
Sharapova was making her comeback at Roland Garros, having been refused a wildcard last year shortly after her return from a 15-month drugs ban.
After a confidence-boosting run to the last four in Rome, she was eyeing her first Grand Slam semi-final since she went on to reach the 2015 Australian Open final.
That never looked like happening as Muguruza dominated from the start.
Sharapova had not played for four days after long-time rival Serena Williams pulled out of their last-16 match with a pectoral injury.
Muguruza, meanwhile, barely played either as Ukraine's Lesia Tsurenko pulled out of their fourth-round match with a hip problem after only 20 minutes.
But the lack of court time appeared to affect Sharapova more as she made a sloppy start.
Three double faults from Sharapova in the opener gifted an early advantage to Muguruza, another in the sixth deuce of an 11-minute third game helping the Spaniard go 3-0 ahead.
With momentum behind her, Muguruza continued to dominate and served out to win the opener set in 42 minutes.
Ruthless Muguruza shows pedigree
Muguruza had not enjoyed a successful clay-court season before arriving in Paris, winning just twice on the surface in Madrid and losing her opening matches in Stuttgart and Rome.
However, she always seems to peak in time for Roland Garros and Wimbledon, having won or finished runner-up at one of the two Slams in each of the past three years.
Now only Halep or Kerber stand in her way of a second final appearance in three years at Roland Garros after she demolished the five-time Slam champion.
Muguruza's three previous meetings with Sharapova had all ended in defeat - including a 2014 Roland Garros quarter-final where Sharapova had also eased to the opening set.
This ruthless victory demonstrated how much Muguruza has matured since that loss.
She refused to let Sharapova gain a foothold this time, breaking in the opening game of the second set, then three times more as the Russian won just 11 points. SHARE THIS STORY USING ANY OF THE BUTTON BELOW ⬇ PLACE YOUR TEXT ADVERT BELOW ⬇⬇⬇