O'Neill believes Van Persie is now United's talisman like Messi is at Barcelona and someone who has that precious ability to bring out the best in those around him.
O'Neill, who worked with Henrik Larsson at Celtic when the Swede helped the Scottish giants to huge success, said: "United have paid close on £30m for a player who had just one year left on his contract, so that might tell you how valuable they perceive him to be.
"But it's not just how the perception is, the reality is that he has been fantastic.
"Honestly, he can get goals out of very little. You always felt that United would give themselves a big edge by getting Van Persie.
"This extra boost that United got in pre-season would have been psychologically massive.
"The number of goals he has scored is incredible. They are a very talented team, but without him, you don't know because Messi is their talisman.
"Van Persie and Wayne Rooney, the two of them are linking up and keeping some excellent players out of the team, and they really are excellent.
"When you have that, it gives the team great confidence that, you might make a mistake or two, as they did defensively against Reading, but with players like Van Persie you always have a chance of winning matches when you have that calibre of player in your side.
"We are making judgements before Christmas here, but if he stays fit, that will make a massive difference to United's challenge."