O'Neil claimed Vidic should have walked - more for persistent yellow card offences than for a straight red for hauling back Demba Ba.
Asked if the Hammers would have held on against 10 men, O'Neil said: "Yeah, I would've thought so. It makes it easier to hold on, obviously.
"But I think the main difference was the changes they made. They were positive changes.
"They didn't cause us too many problems in behind, first half, but as soon as (Javier) Hernandez came on and they brought (Dimitar) Berbatov on as well, it made a massive difference."
Defeat dragged West Ham back into the drop zone and later results also went badly against them.
O'Neil said: "If we'd have done okay and lost 1-0, everyone would have just said, 'That was Man United'.
"Because we were 2-0 up, it makes it feel that little bit harder to take.
"But we've got some big games coming up.
"We'll be ready for Bolton away next weekend and it's a game we fancy getting something from."