But Villa have the best defensive record in the top flight - just 18 goals conceded in 24 games - and shut out the Red Devils in a 1-0 win at Old Trafford in December.
O'Neill said: "It is Manchester United in town and at the moment they are playing particularly strongly.
"Rooney is in fantastic form. He has been an exceptional player for some time. He is probably playing the best he has ever played at the moment, scoring goals as well, which gives you a big boost of confidence.
"He has been a real top quality player for the last four or five years.
"Has he stepped up after the loss of Carlos Tevez and Cristiano Ronaldo? It seems he has taken on even more responsibility and he is thriving on it.
"Yet last season, when United wanted to play him wide right or wide left to help maybe stop the opposition from playing, Rooney was the first one to volunteer.
"Now he (Sir Alex Ferguson) has got him playing basically as a centre-forward, either with Berbatov or on his own. He is up to the challenge and he is just a terrific footballer."
O'Neill has been delighted with the form of Richard Dunne, James Collins, Carlos Cuellar, Luke Young and Stephen Warnock in Villa's defence.
He said: "It will be hard to keep Manchester United at bay but we are going to try our very, very best and we are doing pretty well defensively.
"This time last year, when we were without Martin Laursen, we would have been conceding a lot more goals.
"But I think the three lads coming in the last few days before the transfer dead-line in August (Collins, Dunne and Warnock) has given us a great boost."
Not that O'Neill will be content for his side to adapt a cautious approach against United.
He added: "We will be very dangerous on the counter-attack and United themselves won championships based on counter-attacking football.
"There was nothing wrong with that when they had the players to do so.
"It is not a case of us hanging around our own penalty area waiting for some things to happen on the break. We might be forced back in the game but I also think we are capable of taking the game to Manchester United."
Striker Emile Heskey looks like being ruled out against United with a groin injury suffered in the goalless draw at Tottenham but O'Neill does not expect the England player to be a long-term absentee.
He said: "Emile went for a scan yesterday and the news is pretty good. It didn't show anything really.
"Whether Wednesday comes a bit too early for him, I'm not too sure. He is in the squad at the moment but he didn't train today and probably would be considered doubtful but we will see."
Man. Utd 10/11, Draw 13/5, Aston Villa 11/4