Switzerland's Wawrinka came into the clash having won two of the duo's three clashes at the major, including a draining five-setter in the 2017 semi-finals from which Murray's creaking hip never recovered and eventually forced him to have surgeries.
Having sent Murray packing in straight sets in the opening round four years ago, Wawrinka shot out of the blocks again in the duo's 23rd career meeting by grabbing a break in the first game.
The 2015 champion wrapped up the opening set on the back of a couple of booming serves and pounced in the third game of the second set with a string of heavy single-handed backhands from the baseline to heap the pressure on Murray.
Murray, who at 37 has stated that he is unlikely to play beyond the summer, rode a wave of support at Philippe Chatrier court and battled on but was unable to prevent fellow three-times Grand Slam champion Wawrinka from going two sets up.
A medical timeout for Wawrinka's left calf issue delayed the start of the third set, but 2016 runner-up Murray's movement was also compromised due to an apparent leg issue that allowed his opponent to run away with the contest.
