They came away with four points from the games and finished runners-up to Pep Guardiola's men to send them into the knockout stages for the first time in seven years.
Barcelona are, however, an altogether different prospect. They are perennials at this stage of the competiion. Yet they arrive with a certain amount of fragility at the 59,000 seat Groupama Stadium.
The Catalans are seeking a first away win in the knockout phase in six attempts since a 2-0 victory at Arsenal in February 2016.
"That shows that it is a hard competition," said Barcelona boss Erneseto Valverde.
"But challenges are there to be overcome. We need to come into these games not with our guard down but with our guard up."
Barcelona are seven points clear of Atletico Madrid at the top of La Liga with 14 games remaining.
Lyon are third in the French top flight with 46 points from their 25 matches. They hold the honour of being the only side to have beaten pacesetters Paris Saint-Germain in the league this season.
Nabil Fekir scored the winner in the 2-1 victory on 3 February in Lyon. However the World Cup winner will be absent on Tuesday night through suspension.
"I am not going to deny that he can be a decisive player for them," said Valverde. "He scores goals, provides assists. His is an important absence for Lyon."
Genesio urged his players to rekindle the spirit that brought a famous win at the Etihad and a draw at home against Manchester City.
"The experience can help us," he said. "We played really well in the two games against City. And if we were capable of doing it against them, we can do it again."