Benzema put the visitors 1-0 up shortly after coming on as a second-half substitute at a damp and chilly Stade Gerland, only for Bafetimbi Gomis to equalise seven minutes from time. Gomis's late volley extended Lyon's remarkable unbeaten record against Real to seven matches, but Benzema's away goal makes Jose Mourinho's side slight favourites to progress ahead of the second leg in Madrid on 16 March.
Lyon eliminated Real at the same stage of last season's competition and the nine-time European champions are bidding to end an unwelcome run that has seen them fall in the round of 16 for the last six seasons in a row.
"I feel like I watched a real Champions League match: hard and well contested with very few clear chances due to the defensive rigour on both sides," said Real coach Mourinho. "In the second half we managed to find spaces and, to begin with, we were closer to a second goal than Lyon were to an equaliser. But it sets things up well for the second leg, where we will hope to qualify in front of our supporters."
Having beaten Real in their three previous encounters on home turf, Lyon began the game in enterprising style, their five-man midfield smothering the visitors' attempts to play the ball through the middle. Michel Bastos stabbed a shot over the Real crossbar from a tight angle on the right, Cris hooked wide from just inside the penalty area and Cesar Delgado had a penalty appeal turned down after an untidy foul by Sergio Ramos.
Angel di Maria belatedly called Lyon goalkeeper Hugo Lloris into action with a weak low shot before the France No1 was given slightly more to do by a stinging Cristiano Ronaldo free-kick. It was not long before the hosts were back on the attack, however, and Gomis was guilty of a terrible miss in the 34th minute when he side-footed over an open goal after Iker Casillas spilled a cross from Bastos.
Lyon's re-emergence after half-time drew a thunderous roar from the home fans, but a reminder of Real's attacking threat was quick to arrive as the visitors struck the woodwork twice in a matter of minutes. Ronaldo hit the far post with a dipping free-kick from a seemingly prohibitive angle on the left-hand side, before Ramos sent a header crashing against the crossbar from Mesut Ozil's swinging corner.
Ronaldo's free-kick will have a more lasting impact on the tie, however, as it was awarded for a foul by Bastos on Di Maria that earned the Brazilian a yellow card that rules him out of the return leg. Another Ronaldo free-kick sparked controversy shortly beyond the hour, with the Portuguese adamant the ball had struck the arm of Yoann Gourcuff in the Lyon wall.
Benzema, who left Lyon for the Bernabeu in 2009, received a rapturous reception when he entered the fray but he immediately silenced the generous crowd. Receiving a pass from Ronaldo, he drove across the area in a horizontal line before keeping his cool to beat Lloris with a low shot that Cris vainly sought to keep out with a desperate goal-line lunge.
Lyon's proud unbeaten record against Real looked destined to come to an end until the 83rd minute, when Gomis atoned for his earlier miss by seizing upon a flick-on from a free-kick to volley into the bottom-left corner.