The former Manchester United captain says City's strong Premier League form will "go out of the window" when they come up against the Catalan club, while also citing their extensive experience in Europe.
That experience, Keane believes, will give Barcelona the edge over two legs, with the 42-year-old also fearing for City's ability to retain possession against Tata Martino's side.
And, although Keane says it "wouldn't be a massive shock" if Man City got through, he has "stuck his neck out on Barcelona."
"What Barcelona have over City - despite City making great progress - is that European experience. That might be the difference," he is quoted as saying by the Daily Mirror.
"In a sense, your league form does go out the window because you’re playing against these world-renowned players, the Messis, the Neymars.
"As much as [City] are doing well in the Premier League, this is going to be a different animal.
"Attacking-wise City, particularly at home, have been outstanding. But will they get that much possession? Because Barcelona, no matter who they are playing, seem to dominate that.
"A lot will depend on if they can stop Messi. Then they’ve got a great chance. Obviously I’ve stuck my neck out on Barcelona but if City got through, that wouldn’t be a massive shock either."
Do you agree with Keane's views?
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