Ligue 1 pair Bordeaux and Toulouse suffered major upsets and Paris Saint-Germain also exited the Coupe de France in the last 32.
Attention in the build-up to round 10 had focused on Ludovic Giuly leading out tiny Monts d'Or Azergues against his former club Monaco but it was their fellow minnows who finished the night in the limelight.
Fifth-tier L'Ile Rousse triumphed on penalties against Les Girondins while AS Moulins came from behind to shock Le Tefece.
PSG then lost to struggling Ligue 1 rivals Montpellier on a night of upsets.
Nicolas Maurice-Belay hit the crossbar for Bordeaux before half-time and Henri Saivet's lob beat Florent Menozzi but was cleared off the line by the goalkeeper's brother Dominique.
Mariano's shot was then superbly saved as, despite a late surge, Bordeaux were taken to extra time and eventually spot-kicks by the Corsican side.
Florent Menozzi kept out David Bellion, Bordeaux's second penalty taker, and though Cedric Carrasso saved from Dominique Menozzi, Lamine Sane missed to send Les Girondins out.
Fourth-tier Moulins also upset their top-flight opponents, winning 2-1 at the unprepossessing Stade Hector Rolland.
Eden Ben Basat's opener on the half-hour was cancelled out just after half-time by Sebastien Da Silva, who then wrote his name into club folklore with an 86th-minute winner.
At the Parc des Princes, Daniel Congre's opener was cancelled out by PSG's Edinson Cavani before half-time.
But Victor Montano restored Montpellier's lead in the 69th minute and 2-1 was the way it stayed as Rolland Courbis' relegation-threatened side progressed.
Lyon survived a scare against fourth-tier Yzeure, falling behind with 15 minutes remaining before rallying to win 3-1.
Lamine M'Baye's goal gave Yzeure, conquerors of Lorient in the last round, hope of an even more famous result but Jimmy Briand equalised immediately before Yoann Gourcuff and Steed Malbranque saw Lyon through.
Monaco eased through 3-0 in a game switched from MDA's home stadium in Chasselay - named after Giuly - to the Stade Gerland in Lyon.
Radamel Falcao tapped in the opener before he went off at the interval with a knee injury and his replacement Emmanuel Riviere scored twice.
Giuly twice went close in the second half, grazing a post with a delicious free-kick, but was unable to produce a fairytale goal.