Lyon players celebrateGetty Images
At a glance
Tabitha Chawinga's diving header beats United goalkeeper Phallon Tullis-Joyce in the 12th minute.
Melchie Dumornay's exquisite strike curled into the top corner to make it 2-0 late in the second half, and she added a third in stoppage time.
Melvine Malard's header flew over the crossbar in United's only real chance shortly before half-time.
United have already secured a play-off spot for the knockout stages, while Lyon are on course to qualify automatically if they retain their top-four spot.
Emma Sanders
BBC Sport women’s football news reporter at Leigh Sports Village
Manchester United were easily beaten by eight-time Champions League winners Lyon in a fairly one-sided affair at Leigh Sports Village.
With a play-off spot for the knockout stages already secure, United boss Marc Skinner made five changes to the starting XI, leaving out several big names for the league-phase tie.
However, it was exploited by Lyon in a dominant first half in which United had just one touch in the opposition box - a header from Melvine Malard in the 40th minute that flew over the bar, despite being unchallenged.
Lyon were good value for their early lead, given to them by Tabitha Chawinga's diving header, and the visitors should have extended their scoreline on several occasions before the break.
They did make it 2-0 eventually when Melchie Dumornay curled in a superb strike with 10 minutes remaining, then added Lyon's third, finishing off a cross from the right to confirm a deserved victory for Lyon.
Skinner's changes at half-time - the introductions of England duo Jess Park and Ella Toone, and Sweden midfielder Julia Zigiotti - made a difference, but United still struggled to test Lyon goalkeeper Christiane Endler.
This is United's first season in the Women's Champions League main draw but Lyon's superior quality and experience was clearly evident on the night.
Jonatan Giraldez's side are yet to lose in the competition this season, sitting level on points with Barcelona in second place in the 18-team table with just one game remaining.
The top four qualify automatically to the quarter-finals, while teams sitting fifth to 12th are drawn in a two-legged play-off. United currently sit ninth, in an unseeded spot in the play-offs.
More to follow.
What's next for these teams?
Manchester United host Tottenham in the Women's Super League on Sunday, 14 December (14:30 GMT) before travelling to Juventus on Wednesday, 17 December (20:00 GMT).
Lyon travel to Le Havre on Saturday, 13 December (16:00 GMT) for their next league fixture before hosting Atletico Madrid in their final European league-phase match on Wednesday, 17 December (20:00 GMT).
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Manchester United
OL Lyonnes
Starting XI
91P. Tullis-Joyce
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2A. Sandberg
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3G. George
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4M. Le Tissier
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14J. Riviere
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16L. Naalsund
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20H. Miyazawa
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13S. Awujo
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12F. Rolfö
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28R. Williams
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9M. Malard
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11L. Galton
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8J. Park
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17D. Janssen
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7E. Toone
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18J. Zigiotti Olme
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Starting XI
1C. Endler
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4S. Bacha
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15I. Engen
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18A. Sombath
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33Tarciane
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10L. Heaps
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13D. Egurrola
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22T. Chawinga
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6M. Dumornay
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29J. Brand
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14A. Hegerberg
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11K. Diani
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9M. Katoto
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12A. Lawrence
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8K. Shrader
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20L. Yohannes
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