Murray ended Wawrinka’s reign as champion in the semi-finals 12 months ago but could not engineer a repeat as the Swiss triumphed 6-7 (6/8) 6-3 5-7 7-6 (7/3) 6-1 after four hours and 34 minutes.
It was a rollercoaster of a match, with Murray second best for most of the first three sets but somehow emerging two sets to one in front.
He then looked in control of the fourth but it was Wawrinka who dominated the tie-break and by the decider Murray had nothing left.
It will of course be a disappointment for the world number one not to make a 12th grand slam final but he leaves Roland Garros in much better shape than when he arrived.
Wawrinka, who has won all his previous three grand slams finals, will face either Rafael Nadal or Dominic Thiem on Sunday.
The first set alone had enough drama for a whole match.
Wawrinka made his intentions clear from the off, crushing 12 winners in the first five games, most of them off his forehand.
Murray tried to pin Wawrinka high on his single-handed backhand but was struggling to maintain enough depth on his shots.
Wawrinka made the first move with a break for 5-3, seizing on a tentative approach and flashing a cross-court winner past the despairing lunge of Murray at the net.
But he could not serve it out as Murray again showed off his remarkable defence abilities.
When Wawrinka drilled a forehand into the corner, it looked as if he had saved break point, but Murray scrambled a lob just inside the baseline and his frustrated opponent smashed it long.
Both men contrived to throw away points in an enthralling tie-break - Wawrinka twice getting it wrong with his forehand before, at 5-4, Murray was too casual on a forehand with the court gaping and paid the price.
Wawrinka won a fine rat-a-tat volley exchange at the net to create a set point only to net a backhand.
And he would live to regret it as Murray combined defensive and offensive lobs to move 7-6 in front and then took the set when Wawrinka dumped a return in the net.
The third seed, who was bullish about his chances ahead of the match, surely could not believe he was behind.
But he refocused and, crucially, began to tee off on his backhand during the second set, nailing a winner down the line to break at love in the seventh game.
Wawrinka does not so much hit the ball as bully it, and a forehand return crushed into the corner gave him a fourth game in a row and the second set.
Speaking after a patchy win over Kei Nishikori in the quarter-finals, Murray said: “Sometimes you just have to do what you have to do to win the match. It’s not always about how well you play.”
But finding a way, the Murray mantra, was not working and Wawrinka won the first three games of the second set to make it seven in succession.
Murray succeeded last year by surprising Wawrinka with his aggression and rushing the Swiss, but he was playing this match from several metres behind the baseline.
What Murray never lacks, however, is grit, and just when it looked like the contest was getting away from him, he worked his way back in.
Great hands help, too. No one in tennis anticipates like Murray, and the Scot’s ability not just to get a racket to smashes but to send them back with interest was driving Wawrinka to distraction.
With a combination of inspired defence and some of the best attacking play he has shown all fortnight, Murray won five of the last six games to steal the set from under Wawrinka’s nose.
The Swiss must have been fuming but he weathered a Murray purple patch at the start of the fourth and finished the set back on top.
A poor drop shot cost the world number one in the tie-break, which Wawrinka took with another bulldozing forehand.
And when he won the first three games of the fifth set, breaking Murray twice, it was clear the weary Scot’s race was run.
Murray battled grimly to avoid a love set but Wawrinka finished the match in the manner in which he had played it, with his 87th winner.