The 30-year-old Lausanne native claimed a famous 4-6, 6-4, 6-3, 6-4 victory to secure his second career major after the 2014 Australian Open.
It ended world number one Djokovic's bid to become only the eighth man to secure a career Slam as he slumped to his third defeat in a Roland Garros final in four years.
At 30, 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.
“It's really hard to believe but it has finally happened,” said Wawrinka, who fired 60 winners past the Serb.
“It was the match of my life,” the Swiss said.
“But bravo to Novak, it's a great challenge, the biggest one to play him,” he said.
“It's a special moment for me.”
“It's hard for me to speak right now,” said Djokovic who was in tears on the presentation podium.
“I'd like to say well done to Stan,” he said.
Djokovic said the Swiss “has a great heart and I have all respect for him — he is a deserving winner.”
He aded: “But I'd like to say I will be back next year and I will try again.”
Sunday's shock defeat was only Djokovic's third in 44 outings in 2015 and ended his 28-match win streak.
It was also his eighth loss in 16 finals at the majors.
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 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 compatriot Roger Federer out in the quarterfinals, 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.
Djokovic was playing for the third day in succession having needed five sets to beat Andy Murray in the semifinals.
He looked suddenly jaded and unplugged, fighting off three break opportunities in the second game of the third set.
The Serb dropped serve again to trail 4-2 and when he carved out a break point in the next game it was his first such morsel since the seventh game of the opener.
It was no surprise when Wawrinka wrapped up the set in the ninth game with Djokovic having no answer to his opponent's lethal battery of down the line backhands and pinpoint accurate forehand winners.
Djokovic found a late lease of life for a break at 2-0 and held for 3-0 in the fourth set.
But back stormed Wawrinka, retrieving the break on the back of a 30-stroke rally before Djokovic saved two more break points to go to 4-3.
In a rollercoaster fourth set, the Swiss saved three break points in the eighth game and on the back of three of probably his finest ever backhands broke for 5-4.
And it was another textbook backhand that won him the title on a second match point.