Wawrinka headed into the tournament as one of the favourites following his success at Australian Open, but was stunned by clay-court specialist Garcia-Lopez, who claimed a 6-4 5-7 6-2 6-0 triumph.
Swiss world number three Wawrinka committed an astonishing 62 unforced errors in the match as he became the first Australian Open champion since Petr Korda in 1998 to lose in the first round of the French Open.
The other major surprise on Monday came as ninth seed Kei Nishikori was beaten 7-6 (7-4) 6-1 6-2 by Slovakian Martin Klizan.
Nishikori, who had retired during the Madrid Open final with Rafael Nadal earlier this month, looked short of fitness as he exited the tournament in a match that lasted just one hour and 57 minutes.
But, while two of the top 10 seeds suffered early exits, both defending champion Nadal and world number two Novak Djokovic both progressed with no difficulty.
Nadal won 87 per cent of points on his first serve as he destroyed American Robby Ginepri 6-0 6-3 6-0 to ensure a clash with Dominic Thiem, victor over Paul-Henri Mathieu, while Djokovic racked up 40 winners in a 6-1 6-2 6-4 triumph over Portugal's Joao Sousa.
The longest match of the day came in the shape of a five-set epic between home hope Julien Benneteau and Argentine qualifier Facundo Bagnis, who triumphed 6-1 6-2 1-6 3-6 18-16 in four hours and 27 minutes.
Yet, there was better news for French 29th seed Gilles Simon as he hammered Ante Pavic 6-1 6-1 6-3.
Adrian Mannarino and Benoit Paire gave the home fans more to cheer about with wins over Lu Yen-Hsun and Alejandro Falla respectively, but Nicolas Mahut lost in four sets to Kazakh Mikhail Kukushkin.
Spaniard and 17th seed Tommy Robredo came back from a set down to beat Great Britain's James Ward 4-6 6-4 6-2 6-4 and set up a meeting with France's Kenny de Schepper, who benefited from Albert Montanes' retirement.
Further Spanish success was secured as Feliciano Lopez cruised through by beating Bosnian Damir Dzumhur 6-3 7-6 (10-8) 6-3 and Roberto Bautista Agut comfortably dispatched Paolo Lorenzi of Italy 6-3 7-5 6-2.
Marcel Granollers played through just four games with Ivan Dodig before the Croatian's withdrawal, but Dodig's compatriot Marin Cilic eased through 6-0 6-3 7-6 (8-6) against Pablo Andujar of Spain.
Italy's Fabio Fognini started his campaign by overcoming German Andreas Beck 6-4 6-4 6-1, and Latvian Ernests Gulbis rallied after losing the first set to knock out Pole Lukasz Kubot 4-6 6-4 7-5 6-1.
Dutchman Robin Haase was a straight-sets winner over Nikolay Davydenko of Russia, whose countryman Teymuraz Gabashvili eliminated Canada's 30th seed Vasek Pospisil 6-4 6-2 6-3.
Jiri Vesely beat Lukas Rosol in the all-Czech clash of the day, while Germany's Tobias Kamke won three tight sets with Slovak Miloslav Mecir Jr.
Elsewhere in the draw, there were wins for Donald Young, Leonardo Mayer, Thomaz Bellucci, Alejandro Gonzalez and Jurgen Melzer, but the matches between Stephane Robert and Kevin Anderson and Axel Michon and Bradley Klahn have been moved to Tuesday.