The 30-year-old Swiss claimed a famous 4-6, 6-4, 6-3, 6-4 victory to secure his 2nd career major after the 2014 Australian Open.
It ended world number one Djokovic's bid to become only the 8th man to secure a career Slam as he slumped to his third defeat in a Roland Garros final in four years.
Wawrinka became the oldest champion in Paris since Andres Gomez in 1990 after just his fourth win in 21 meetings against the Serb.
Sunday's shock defeat, meanwhile, was only Djokovic's third in 44 outings in 2015 and ended his 28-match win streak. Djokovic, playing in his 16th Grand Slam final to Wawrinka's second, had the Swiss player under siege in the first set.
Eighth-seeded Wawrinka had to save break points in the opening game - which featured a 39-shot rally - and the fifth.
But the world number one broke through for a 4-3 lead when Wawrinka served up a double fault. The battling 30-year-old Swiss saved two set points in the 10th game - one after a botched forehand put-away by Djokovic - and then carved out a first break opportunity.
That was swiftly saved and the Serb gobbled up the opener after 43 minutes, celebrating with a mighty, arena-shaking roar.
Wawrinka cranked up the forehand winners early in the second set but was unable to convert two break points in the fourth game as Djokovic's renowned powers of recovery made him an intimidating target to pass.
Wawrinka, who had knocked Roger Federer out in the quarter-finals, saw another break point disappear in the sixth game.
In the eighth, it was the same story as Djokovic saved another break point causing Wawrinka to violently smash his racquet into the net in frustration.
But he wasn't to be denied as Djokovic surrendered the set in the 10th game with a wild backhand, collecting a warning for destroying his racquet in the Paris clay.