Murray, playing in only his second major since undergoing hip resurfacing surgery, proved no match for the 16th seed, who dropped just six games on the way to a 6-1 6-3 6-2 victory.
Having been given a wildcard to the prestigious tournament, Murray was drawn against the Swiss, who coincidentally was his previous opponent at Roland Garros in the semi-final three years ago.
The brutal match proved a tale of woe for both players, with Murray's hip issues initiating thereafter, while Wawrkina also needed knee surgery that looks to have saved his career.
But while the match-up once resembled a true blockbuster at the top of the men's game, Wawrinka who needed just one hour and 37 minutes to breeze through a routine opening round.
— Roland-Garros (@rolandgarros)September 27, 2020
Having been pushed back by four months due to the outbreak of coronavirus, the usually scorching weather inside the famous Philippe-Chartier Court was replaced by much colder conditions.
In fact, a sluggish Murray was sporting leggings underneath his shorts as he slumped to a 6-1 defeat in the opening set, winning just 11 points on serve.
Though picking up in the second set, he found himself two sets to love down, before a break immediately in the third ultimately put to rest any chances of a comeback.
And after failing to capitalise on three break points having reduced Wawrkinka to 0-40 in the following game, Wawrinka then steamrolled to victory, booking his place in the second round with an ace.
Shortly after Murray's defeat, British women's no1 Johanna Konta also made an early exit from Roland Garros.
The 29-year-old - seeded ninth for the tournament - lost 6-3, 6-3 to talented American teenager Gauff, 16, in a disappointing display containing plenty of errors.
Gauff was making her main draw debut in Paris and will play qualifier Martina Trevisan in round two.
"It's unfortunate that it happened here but I just didn't play too well," Konta said, per Sky Sports.
"I think nothing was working consistently enough. I think I was trying to do good things, and I had semi opportunities to try and get something going, but I just didn't find a good enough level to be able to get where I wanted today."
Fellow British no1 Dan Evans is also out of the French Open following a 1-6 6-1 7-6 (7-3) 1-6 6-4 defeat to Japan's Kei Nishikori on day one.