Lyon stunned the reigning Premier League champions early in the campaign, winning 2-1 on the road after racing into a two-goal lead through Maxwel Cornet and Nabil Fekir.
Only a brilliant Ederson save denied Memphis Depay a third in that match and Genesio will send his side out to take on City at their own game again at the Groupama Stadium.
"We must play the game with complete focus," Genesio told a news conference. "This is a team that is superior to us on paper. We'll have to be at 150 per cent to win.
"Manchester City are one of the favourites to win the Champions League. They are one of the best European teams, but we will play with ambition - it's the only way to trouble them again. We have to believe in ourselves.
"We have to play. If we just defend, we will suffer and we will concede. That much is obvious. We must play with ambition in front of our home fans and have no regrets."
Lyon goalkeeper Anthony Lopes also excelled in the reverse meeting, however, and Genesio acknowledges his side will need more of the same from the Portugal international on Tuesday.
"Our keeper allowed us to stay in the game [in Manchester]. He gives us a lot of confidence," Genesio said. "We'll need another big performance from Antho Lopes, as in the away game."