Barca will visit the Etihad for the first-leg this week.
Keane said: "What Barcelona have over City - despite City making great progress - is that European experience. That might be the difference.
"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."