Wawrinka's semifinal opponent on Friday will be heavy French crowd favorite Jo-Wilfried Tsonga, who ousted U.S. Open runner-up Kei Nishikori in five sets on Day 10.
Wawrinka entered Lenglen Court on Tuesday with a lifetime mark of 2-16 against the 17-time Grand Slam champion, but exited with a dominant 6-4, 6-3, 7-6 (7-4) victory that put him into his first French Open semifinal.
Federer had won the past three meetings with his countrymate, including a 6-4, 6-2 thumping in a semifinal in Rome earlier this spring. He had also been 4-0 against Wawrinka at major tournaments, which included fourth-round victories at Roland Garros in 2010 and 2011.
However, on Tuesday, the tables were completely turned.
Wawrinka was the clear aggressor throughout the match in blustery conditions. He blasted 43 winners to just 28 for Federer and kept the 2009 French champion on his heels for most of the match.
Federer failed to convert any of his four break-point opportunities and was broken three times by Wawrinka, who last beat Federer for the Monte Carlo title in 2014. His only other victory against Federer also came in Monte Carlo, five years earlier.
The iconic Federer failed to break serve in a Grand Slam match for the first time since 2002.
Wawrinka, a first-round loser last year on the famed red clay in the French capital, was a quarterfinalist in 2013.
Federer dropped serve for the first time in the third game on Tuesday, then failed to convert a break point in the 10th game before Wawrinka sealed the set. Wawrinka then won four straight games to finish the second set.
The third went to a tiebreak and Wawrinka took control on an overruled line call. A Wawrinka forehand was called out, but the chair umpire said it was good for a 4-3 Wawrinka lead.
Federer was clearly unhappy with the decision and went on to lose the next two points, all but sealing his fate.
"I tried many things," Federer said. "One of them was trying to put it up high. Another one was trying to chip it shorter. Another one was trying to hit through the wind. Obviously I was not going to, you know, leave the French Open without having tried everything out there. So it was tough, you know. Would have loved to have won the breaker, would have loved to come back in the first set, but wasn't so.
"Stan was clutch on the big points and really didn't give me much, so it was a credit to him for playing so well today."
Wawrinka will play in his second major semifinal of the year. He lost to eventual champion Novak Djokovic in the Australian Open semis while trying to defend his lone career Grand Slam title.
The former world No. 1 great Federer has now lost in the quarterfinals or earlier in his last three visits to the French Open. He was also a third-round loser in Melbourne earlier this year.
Meanwhile, the 30-year-old 14th-seeded former Aussie Open runner-up Tsonga reached his second French Open semi in three years by outlasting the fifth- seeded Nishikori, 6-1, 6-4, 4-6, 3-6, 6-3.
Tsonga appeared to be on his way to a straight-set win, with a seemingly comfortable two-set lead, but Nishikori found the range on his big forehand en route to claiming a pair of sets of his own.
But if you were expecting a nail-biting fifth-set showdown, it didn't happen, as Tsonga dominated, much to the delight of the home fans.
Tsonga broke for a 3-1 lead in the fifth and never looked back. The French star earned his first match point when Nishikori sent a forehand long, and converted on it when his Japanese counterpart floated a backhand long, which prompted an on-court celebration by the affable Tsonga.
The Tsonga-Nishikori match was interrupted, with Tsonga leading 6-1, 5-2, when three spectators were injured after a piece of metal fell from the scoreboard at Court Chatrier. The injuries were described as minor.
The situation delayed the quarterfinal bout for about 30 minutes and fans eventually returned to their seats.
Video of the incident showed a long sheet of metal, roughly 15 feet wide, falling from the top of the scoreboard in one corner of the stadium. The sheet, which was covered in spikes to deter birds, appeared to have been dislodged by the wind.
Tsonga will face Wawrinka in the final four. The two have split six career ATP matchups, including a split of two meetings at Roland Garros. The Swiss topped the Frenchman in the round of 32 in Paris in 2011 and Tsonga bested Wawrinka in the round of 16 the following year.
Two more quarterfinals will be staged on Wednesday, when top-seeded Novak Djokovic takes on sixth-seeded former world No. 1 and nine-time French Open king Rafael Nadal and third-seeded Andy Murray tangles with seventh-seeded 2013 Roland Garros runner-up David Ferrer.
The 14-time major champion Nadal, who's an incredible 70-1 lifetime at the French, will celebrate his 29th birthday on Wednesday.
Djokovic lost to Nadal in two of the previous three French Open finals, including last year. Nadal leads their lifetime series 23-20, including 9-3 at the Slams and a perfect 6-0 record at Roland Garros.
Djokovic currently holds the Aussie Open and Wimbledon crowns and has won his last 26 matches on tour overall, including a 13-0 mark on clay this year.
The eight-time major champion from Serbia still needs a French Open title to complete a career Grand Slam.
Nadal has won five straight French Open titles, this following a run of four straight championships from 2005-2008. His lone loss at the French came in the fourth round against Swede Robin Soderling back in 2009.
The two-time Grand Slam titlist Murray, who's a perfect 14-0 on clay this year, is 9-6 lifetime versus Ferrer, but has never beaten the Spaniard on clay.
Murray was January's Aussie Open runner-up to the high-flying Djokovic.