Lyon's hopes of a domestic Cup double were ended as Remi Garde's side were eliminated from the Coupe de France at the last 16 stage, losing 2-1 after extra time to second-tier Lens.
OL took the lead at the Stade de Gerland when Jimmy Briand headed home with just nine minutes played, and it looked like that goal would be enough to take them through to a quarter-final tie away to Monaco next month.
However, Lens were handed a lifeline when Mehdi Zeffane brought down Adamo Coulibaly inside the penalty area a minute into injury time, and Pierrick Valdivia - who started his career with Lyon - converted from the spot.
Lens, who were French champions in 1998 but are currently battling to win promotion back to Ligue 1 after a three-year absence, went on to win the tie in extra time.
The decisive moment arrived in the 94th minute when young defender Jean-Philippe Gbamin took advantage of hesitant goalkeeping by Remy Vercoutre to head home a corner.
While Lens can look forward to a trip to the principality next, Lyon's hopes of silverware now appear to rest with the Coupe de la Ligue, in which they will meet Paris Saint-Germain in the final in April.
Only four Ligue 1 sides made it through to the quarter-finals, with Monaco advancing thanks to a 1-0 extra-time win at Cote d'Azur rivals Nice on Wednesday, in which Dimitar Berbatov scored the winner, his first goal since arriving from Fulham last month.
Rennes will meet Lille in the only last-eight tie between two top-flight sides, while 2009 winners Guingamp will go to Cannes.
Fourth-tier amateurs Cannes, the club where Zinedine Zidane started his career, knocked out Saint-Etienne on penalties in the last 64 and followed that up by beating Montpellier 1-0 after extra time on Tuesday.
Montpellier had beaten PSG in the previous round but came up short on a poor pitch on the south coast, although they were also left to rue a missed penalty by Mbaye Niang in extra time.
The other quarter-final tie will see Angers, of Ligue 2, travel to Moulins, an amateur club from central France.