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Kosovare Asllani’s second goal for the Club had cancelled out Saki Kumagai’s opener but goals from Dzsenifer Maroszan and Eugenie Le Sommer handed the reigning champions a strong advantage to take into the return leg.
With European newcomers City heading into the clash as underdogs, manager Nick Cushing explained beforehand he felt there was no pressure on his side but that he was relishing the chance to test himself against the current holders.
The French outfit proved why they are regarded as the best team on the continent, as the visitors showcased their attacking prowess with a display of direct, quick-passing football.
In their six matches en route to the final, Lyon scored 29 goals and their lethal streak continued as they opened the scoring from the spot with barely a minute gone.
The Blues had already twice cleared off the line before referee Katalin Kulcsar adjudged Carli Lloyd had handled in the area and Kumagai stepped up to convert the penalty.
It was the worst possible start.
Ada Hegerberg then forced Karen Bardsley into a fine save and the hosts were shocked into life.
On ten minutes, City pulled level. Having won back possession just past the halfway line, Toni Duggan assessed her options before executing a pinpoint through-ball to Asllani, whose effort took a slight deflection off Griedge Mbock Bathy and bounced home.
The respite lasted only six minutes though as Lyon restored their advantage, netting their second away goal.
Bardsley had done well to deny Camille Abily already but was helpless when the midfielder cut back moments later for Dzsenifer Marozsan to side-foot into the far corner.
The Germany captain then went in search of her second but the busy Bardsley kept City in the game.
The England shot-stopper was called into action again after the break, rushing off her line to block Alex Morgan’s attempt, with Lyon seeking to extend their advantage.
Manager Gerard Precheur introduced Le Sommer, who already had five goals in six appearances in the competition, on 56 minutes – and it paid dividends.
The forward netted her sixth in seven with a drilled effort, ensuring City have a mountain to climb in the second leg.
What it means
City head into next Saturday’s second leg tie needing to score three more than Lyon to qualify. A 3-1 win would take the tie to extra time.
Barcelona or PSG await the winners in the final in Cardiff on 1 June.
Cushing made two changes to the side that booked their place in the FA Cup final at Wembley with a 1-0 win over Liverpool on Easter Monday, as Duggan and Asllani replaced Jane Ross and Izzy Christiansen.
The England star will lock horns with the likes of Eugenie Le Sommer, Alex Morgan and Ada Hegerberg as Man City Women do battle with Lyon in the Champions League semi-finals.
The Blues host the European title holders in the first leg of their last four clash on Saturday (2pm), in their first season in the competition.