The American's win also snaps Barty's winning streak at an impressive 15 matches in a row - dating back to her French Open triumph and including a Birmingham title along with way.
And Coco Gauff's dream run came to an abrupt end when the consistency of seventh seed and former world number one Simona Halep proved a step too far for the 15-year-old American.
Also joining Nadal in the last-eight was his compatriot Roberto Bautista Agut who reached his first Wimbledon quarter-final and second at the majors this year when he defeated France's Benoit Paire 6-3, 7-5, 6-2.
She says Riske was just a better player on the day. And while that might be enough to get even the best of us down, Barty took the opportunity to present a upped chin, a positive attitude, and a song in the ole' heart thanks to her now-customary post-match Disney quote.
Yet Riske broke in the fourth game of the second set and then again in the eighth as Barty struggled to execute in the face of relentless pressure from the American.
Barty fell apart thereafter - her first serve percentage dropping to just 40% and two breaks allowed Riske to level the match.
Thank you Ash Barty for reminding us of the best in us, and encouraging us to keep things in perspective.
The 23-year-old said she would have a break after Wimbledon, and maybe a beer with her team. Barty's loss means that her recently claimed world No. 1 ranking is now up for grabs.
Muchova won the last three games of her match against Pliskova and converted her third match point with a return that clipped the net cord.
After withdrawing from her scheduled third-round doubles match on Tuesday citing an arm injury, Barty's bigger concern is getting her mind and body ready for the US Open starting on August 26.
French Open champion Barty, bidding to become the first Australian champion at Wimbledon since 1980, lost 3-6, 6-2, 6-3 to the world number 55.
Barty began imperiously, booming four consecutive aces in her opening service game and marching through the first set. Martic called for medical treatment on her left leg after the first game of the second set and her movement appeared to be hampered the rest of the way.
"I feel like I've been there in every moment, looking to impose myself".
The final grand slam of the year gets underway on August 26.
Riske was thrilled with the result and said she didn't want the tournament to end despite playing the World's No 1 player. "But that's not the case", she said.
"I think for me personally, no, I haven't lived my life any differently", she said.