Lyon's tactic of defending in numbers frustrated the home side early on. But Ronaldo broke the deadlock when he pounced on a loose ball in the box and squeezed the ball past Gregory Coupet.
Lyon came forward more after the break and almost levelled when Kader Keita's shot thumped against the base of the post but United held on to progress.
It was by no means United's most stylish victory in Europe but their manager Sir Alex Ferguson will not mind one bit after seeing his side equal Juventus' Champions League record of 10 straight home wins.
The pace of Ronaldo and Nani on either wing always looked their most likely route of finding a way through the visitors' well-organised defence and brought them the best early openings. First Ronaldo broke down the right and left Fabio Grosso sliding in his wake but he failed to pull the ball back in time and was crowded out inside the area.