Carlos Tevez struck a crucial late away goal for Manchester United after Karim Benzema looked to have given Lyon a Champions League first-leg advantage.
Ryan Giggs - in his 100th Champions League game - sent Wayne Rooney clear for the best chance of a cagey first half, but Gregory Coupet saved well.
United were stunned soon after the break when Benzema turned and fired brilliantly past Edwin van der Sar.
Cristiano Ronaldo had a free-kick tipped over before Tevez blasted home.
Sir Alex Ferguson will be delighted to come away on level terms after an uncomfortable evening in France, and his team are favourites to progress from the return leg of this last-16 tie in a fortnight.
The United boss will be wary, however, of the cutting edge Lyon possess in Benzema, a man his club have been constantly linked with.
His 24th goal of the season appeared to have eased the pressure on their manager Alain Perrin after a dressing down from outspoken owner Jean-Michel Aulas earlier in the week.
606: DEBATE
Aulas craves European success after achieving domestic domination - Lyon are challenging for a seventh straight Ligue 1 title - but his team have shown defensive vulnerabilities this season.
And there was enough fallibility about the hosts to excite the likes of Anderson, Ronaldo and Rooney in the first half.
But despite that, and for all the possession they enjoyed, the English champions managed to conjure up only one truly outstanding opportunity to punish that backline.
Giggs's superbly weighted pass was controlled majestically by Rooney, who raced through on goal only to see his shot blocked by Coupet's legs.
Benzema was generally well contained by Nemanja Vidic but United were guilty on several occasions of affording the prolific marksman time and space in the opening period.
He was left alone at a Juninho corner but fired tamely at Van der Sar, and then side-footed just over the bar after Francois Clerc found him in space on the edge of the penalty area.
And after United had made the early running in the second half he demonstrated just why United and the rest of Europe's elite have cast their eyes towards him.
There appeared no danger when Jeremy Toulalan played a hopeful pass towards him on the edge of the area but the 20-year-old turned and fired a rasping drive into Van der Sar's left corner in a flash to stun Ferguson's men.
The United boss took off Giggs - who was struggling after picking up a knock late in the first half - and Paul Scholes, and threw on Nani and Tevez to add an even more youthful and pacey look to his side.
The intention was clear: to throw everything at Lyon's suspect rearguard - but, if anything, the home side looked capable of adding to their lead.
Clerc forced a save from Van der Sar with a powerful drive and free-kick specialist Juninho was inches away from a second when his 35-yard effort deviated just wide after landing in front of the United keeper.
United recovered from that to press vigorously late on and after Coupet tipped over a vicious Ronaldo free-kick, Lyon made a hash of the resulting corner.
The ball deflected off substitute Fred to Tevez, who was in acres of space to gleefully smash home and put his team in pole position to reach the last eight.
Lyon: Coupet, Reveillere, Squillaci, Boumsong, Grosso, Clerc (Ben Arfa 78), Juninho (Bodmer 73), Toulalan, Kallstrom, Govou, Benzema (Fred 83).
Subs Not Used: Vercoutre, Cris, Delgado, Keita.
Booked: Reveillere, Toulalan, Boumsong.
Goals: Benzema 54.
Man Utd: Van der Sar, Brown, Ferdinand, Vidic, Evra, Ronaldo, Scholes (Tevez 65), Hargreaves (Carrick 78), Anderson, Giggs (Nani 65), Rooney.
Subs Not Used: Kuszczak, Saha, O'Shea, Fletcher.
Booked: Hargreaves.
Goals: Tevez 87.
Att: 39,230
Ref: Luis Medina Cantalejo (Spain).
BBC Sport Player Rater man of the match: Manchester United's Carlos Tevez on 7.69 (on 90 minutes).
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