In the first meeting of Grand Slam champions in the first round of any major tournament since 2012, Wawrinka beat Murray 6-1, 6-3, 6-2 in a little more than 1½ hours at Court Philippe Chatrier.
Wawrinka compiled a 42-10 edge in total winners while making one more unforced error than Murray, 27-26.
This was the 21st matchup between the pair. One of those previous meetings came in the 2017 French Open semifinals, won by Wawrinka.
Neither man has really been the same since. Wawrinka, 35, has had multiple knee operations, and Murray, 33, has had two hip operations.
Wawrinka won here in 2015 and Murray lost the final to Novak Djokovic the following year.
Sunday's match tied for the fewest games Murray has won in a match at a major. He acknowledged that he may never be the same player he once was following his hip issues, but didn't cite that as the reason for the loss.
"I served under 40% first serve in play. That's just not good enough, especially against someone as good as Stan," Murray said. "That allows who you're playing to dictate points. That's got nothing to do with my [resurfaced] hip. I assume I probably moved better before I had a metal hip, but mistiming my returns and serving just 38% has nothing to do with that."
Earlier in the day, David Goffin became the first seeded player to be knocked out of the event.
The 11th-seeded Belgian lost 7-5, 6-0, 6-3 to 19-year-old Italian Jannik Sinner, who beat Goffin for the second time this year after winning on hard courts at Rotterdam in February.
Sebastian Korda, a qualifier whose father, Petr, won the 1998 Australian Open and was the runner-up at the 1992 French Open, has the first main-draw Grand Slam match win of his career. Korda, 20, beat Andreas Seppi of Italy 6-2, 4-6, 6-3, 6-3.
Korda now faces another American, 21st-seeded John Isner.
Isner advanced by beating Elliot Benchetrit 6-4, 6-1, 6-3.
Alexander Zverev has won his first match since blowing a two-set lead and losing a fifth-set tiebreaker in the U.S. Open final.
Zverev was plagued by double-faults at the U.S. Open but was just fine Sunday, with only two. He hit 10 aces and only was broken once by Novak.
That match finished shortly after the longest contest of Day 1 wrapped up: Juan Ignacio Londero emerged to win a 14-12 fifth set after nearly five hours against Federico Delbonis in an all-Argentine matchup.
Londero won 6-4, 7-6 (1), 2-6, 1-6, 14-12.
The French Open is the only Grand Slam tournament that does not use tiebreakers in the final set.
Nishikori, 30, has reached the quarterfinals at Roland Garros three times, including last year.
Information from The Associated Press was used in this report.