Djokovic entered Philippe Chatrier as strong favourite to win his first title at Roland Garros and complete a career grand slam but Wawrinka turned the form-book upside-down with a 4-6 6-4 6-3 6-4 victory.
The loss brings an end to Djokovic’s 28-match unbeaten streak and means the eight-time major champion’s winless run in Paris extends to 11 attempts.
“Obviously it was not easy to stand there as a runner-up again but I lost to a better player who played some courageous tennis and deserved to win,” Djokovic said.
“I probably could have played better in some moments, more aggressive.
“It wasn’t easy conditions but still, he took his chances whenever they were presented.
“He just played some really good tactical tennis and also very aggressive shots in some break points, like at four-all in the fourth, the winner passing shot down the line.
“All I can do is to say, ’well done’. He deserves it.”
Djokovic looked to have come through his toughest tests in the tournament, having beaten nine-time champion Rafael Nadal in the quarter-finals and then Britain’s third seed Andy Murray in the last four. The clash with Nadal was billed as a potential championship decider while his victory over Murray went to five sets and spanned two days, giving Wawrinka an additional day’s rest.
“I don’t want to come up with excuses, saying these two matches took a lot out of me,” Djokovic said.
“I don’t think that’s fair to Stan. I don’t think that’s fair to sit here and whine about now what has happened. Certainly those two matches were very big in terms of physical demand and mental, emotional, as well. But, still, I was today feeling pretty fresh as much as I could. I was ready to go out and fight, and I have done so.
“Maybe in some important moments I didn’t feel I had that explosiveness in the legs, but at the end of the day he was just a better player.”
Meanwhile, Serena Williams said she considered her French Open victory the most difficult of all her grand slam triumphs after she almost withdrew from the final through illness.
Williams held off a late fightback from Lucie Safarova to win 6-3 6-7 (2/7) 6-2 and clinch her third title at Roland Garros — and her 20th grand slam overall.
The world number one showed few signs of weakness during her victory on Court Philippe Chatrier, despite her preparation being ravaged by symptoms of flu.
“Is it the most difficult grand slam I’ve ever won? For sure,” Williams said.
“When you have the flu, your whole body aches. That’s kind of what I have been dealing with.
“Even now I just really don’t have any energy and I just want to go to bed.”
The victory means Williams is now two short of Steffi Graf’s 22 major titles and four away from Margaret Court’s all-time best 24.