In a titanic tussle which lasted four hours and 34 minutes, Wawrinka was able to outlast Murray to run out a 6-7 6-3 5-7 7-6 6-1 winner.
Wawrinka was generally the better player throughout with 87 winners being recorded, but Murray will take the positives from another tremendous display at Roland Garros only to see the heavier hitting of his opponent winning out.
Murray claimed the opening set on a tie-break after Wawrinka had failed to serve it out at 5-3, but Wawrinka broke twice during the second to level the contest.
He raced into a 3-0 advantage in the third but Murray started to produce some of his best tennis of the year and somehow claimed the set 7-5 to move closer to a second successive final.
However, neither player could create a break point during a fiercely-contested fourth and during the tie-break, there were signs that Murray was beginning to wilt as the clock ticked past the four-hour mark.
He failed to recover from a miscued drop shot at 3-2 down in the tie-break and barely 20 minutes had passed by the time he had dropped serve three times in the decider.
The Scot managed to avoid a final-set bagel with a break of his own but Wawrinka was not to be denied as he gave himself an opportunity to claim a second crown in Paris.