Lyon picked up a third successive home win over Real in the Champions League after the Cameroon midfielder drove a stunning 25-metre shot into the top corner of the net in the 47th minute.
Real, who last reached the quarter-finals in 2004, dominated possession but failed to create many chances despite Cristiano Ronaldo's efforts up front.
"Lyon were physically very strong, they ran a lot and prevented us from playing our game. We weren't able to find the solutions," Madrid coach Manuel Pellegrini told reporters.
"This is a bad result for us as we conceded a goal and weren't able to score one. We'll have to put our game in order in the second leg but I have confidence in my players and I am sure we are able to do it," he added.
"We played a really good game tonight against a good team and we managed to play at a higher level both individually and collectively," he told reporters.
"I just slightly regret that we did not score a second goal after the break. The most important part of the job is still to come. There is a second leg and the only positive result is to qualify," he added.
Ronaldo tried to set up Gonzalo Higuain in the box with a clever back-heel but Lyon's defenders reacted more quickly than the Argentine striker.
