Goals from Maxwel Cornet and Nabil Fekir gave Lyon a shock 2-1 win over the Premier League champions in September, and a repeat success at home would send them through to the knockout stages.
"My advice to the players is to play without any thoughts in the back of their minds," Genesio told reporters at the Groupama Stadium on Monday.
"We are facing a team superior to us on paper but we saw in the first leg we're able to win and we hope to do the same thing again tomorrow."
Lyon are the only team this campaign to score more than once against Pep Guardiola's City, who top Group F on nine points after reeling off three wins in a row following their matchday one setback.
"We need to believe we can win and play to our strengths," said Genesio. "We respect Manchester City because they're a really strong team.
"They are one of the favourites for me, one of the three or four who can win the competition. But we've already beaten them in the first game so we need to have this ambition and keep them on their toes.
"The only way to put them in trouble is to play. We can't just defend because it takes just one goal to change the game. We can only do our best and not have any regrets," he added.
Lyon are second in the group after three successive draws and Genesio faces a late decision over the fitness of influential captain Fekir, with the World Cup winner hampered by a groin injury.
"Nabil is our captain and so one of our most important players, and he is indispensable to the team," he said.
"He needs to be at 100 percent though. We'll have a chat tonight after training and we'll see how he's feeling.
"He ran yesterday. We'll run a final test tonight because when you have such a high level game it's important to test beforehand."
Defender Jason Denayer will come up against his former club, although the Belgium international never made a first-team appearance for City despite spending five years on their books prior to joining Lyon in August.
The 23-year-old moved to City as a teenager in 2013 but was sent on loan to Celtic, Galatasaray twice and Sunderland during his time at the club.
"I had a good time there and picked up a lot of experience," said Denayer, who scored the winner in Friday's 1-0 league victory over bitter rivals Saint-Etienne.
City have scored 40 goals in 13 Premier League outings this term and found the net nine times in their double-header with Shakhtar Donetsk to seize control of the group.
"We'll try do our best defensively and we'll have to do our all to stop them from scoring," admitted Denayer.
"They're a team with huge attacking potential. We'll certainly have to suffer, but it's up to us to take the ball out and worry them."