Sir Alex Ferguson's side had to endure a nervy second-half, however, as Lyon hit the post but his side hung on to equal Juventus' Champions League record of 10 straight home victories.
The winner came from Cristiano Ronaldo in the 41st minute - his 30th goal of the season in all competitions.
Man Utd: Van der Sar, Brown, Ferdinand, Vidic, Evra, Fletcher, Carrick, Anderson (Tevez 70), Ronaldo (Hargreaves 90), Rooney,Nani.
Subs Not Used: Kuszczak, Saha, Park, Scholes, O'Shea.
Booked: Evra, Nani, Fletcher.
Goals: Ronaldo 41.
Lyon: Coupet, Clerc, Squillaci, Cris, Grosso, Ben Arfa, Juninho, Toulalan, Kallstrom (Fred 79), Govou (Keita 67), Benzema.
Subs Not Used: Vercoutre, Bodmer, Delgado, Mounier, Boumsong.
Booked: Grosso, Squillaci.
Ref: Roberto Rosetti (Italy).