An imperious Muguruza made only 15 unforced errors to Sharapova's 27 and broke six times to set up a showdown with Simona Halep, knowing a victory would put her on top of the world rankings.
"I never gave up".
"I think for me it's been being smart about it", Keys said. Halep has won 12 of her last 14 matches on clay court.
Maria Sharapova's return to the French Open ended in a crushing defeat when Garbine Muguruza emphatically silenced the shrieking Russian at Roland Garros. The victor earns a berth in the final at Roland Garros, plus the number one ranking that now belongs to Halep.
Sharapova was due to meet the 23-time Grand Slam champion on Monday in the fourth round, but her opponent pulled out with an arm injury.
Kerber, 30, earned a double break in the first set but Halep recovered to 5-5 only for the pair to exchange a further break before Kerber won the tie-break.
"When you're facing somebody that also has an aggressive style of game", Muguruza said about facing Sharapova, "I think it's about who takes the command, who takes the first opportunity".
It is the first time that two American women have reached the last four at Roland Garros since 2002, when Serena Williams beat sister Venus in the final, after a semi-final win over Jennifer Capriati.
Nadal was broken three times and lost the opening set of his quarterfinal Wednesday against 11th-seeded Diego Schwartzman of Argentina by a score of 6-4.
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Kerber is a two-time Grand Slam champion.
On Court Suzanne Lenglen, Marin Cilic and Juan Martin del Potro were locked in a first-set tiebreak when play was called off.
She took the second 6-1 to record her first career win over Sharapova and heads into the semi-finals in excellent form.
"I don't feel I'm favorite for this match, because she's played better than I have this year", Muguruza said of her next match against Halep.
The Romanian, who lost in last year's final at Roland Garros, defeated Kerber 6-7 (2) 6-3 6-2 to book a clash with Garbine Muguruza in the last four.
Kerber got off to a flying start. "She had a lot more depth in the ball".
"And now it's just - it's good to be able to play all the time for that, but every week there is a new chance, there is a new thing". ". Coming into this part of the year, I was losing a few first-round matches, matches that I wanted to be winning, of course".
On Wednesday, Halep looked anything but the top seed, slipping 4-0 down in the first set before she rallied to defeat Kerber, a two-time major victor who had exited in the first round in Paris in the last two years.