Oxlade-Chamberlain, making his first Premier League start, was by far Arsenal's best player in the first half and also set up Robin van Persie for the Gunners' equaliser in the second period after Antonio Valencia had put Manchester United ahead.
Wenger's decision to substitute the 18-year-old for Andrey Arshavin in the 74th minute was met with a loud chorus of boos from the home fans.
Even Arsenal skipper Van Persie looked at odds with his manager on the decision, appearing to mouth "no" when the board noting Oxlade-Chamberlain's exit was raised by the fourth official.
The move backfired, with Arsenal losing their attacking impetus down the left flank with Arshavin's arrival. The Russian then let Valencia slip by him at the other end, allowing the Ecuadorian to cross for Danny Welbeck to tap home United's winner.
However, Wenger stood by the decision to remove Oxlade-Chamberlain.
"I can understand that the fans are upset about the substitution, especially when it doesn't work, but he (Oxlade-Chamberlain) had started to fatigue," Wenger said.
"He was sick in the week. Arshavin is captain of the Russia national team.
"You have an 18-year-old kid making his first Premier League start and a player who's captain of his country and they are querying the substitution? Let's be serious.
"I've been a manager for 30 years and have made 50,000 subs. I do not have to justify every decision I make. I stand up for it."
Wenger's men now sit five points adrift of fourth-placed Chelsea, and with a difficult fixture list ahead seem to be in real danger of missing out on a top-four position - a scenario which the 62-year-old described as a "disaster" on Friday.
"It leaves us in a very difficult position. It's a game we couldn't afford to lose," Wenger said.
United never looked like losing thanks to some questionable defending from Arsenal's depleted back four.
Nani, Michael Carrick and Ryan Giggs all performed well in midfield and when the veteran Welshman crossed for Valencia to nod home in first-half injury-time, United looked set to run riot.
Gunners goalkeeper Wojciech Szczesny was kept busy in the second half and United should have won by a bigger margin.
With fixtures against Liverpool, Chelsea and Tottenham on the horizon, United boss Sir Alex Ferguson was delighted to keep within three points of league leaders Manchester City, who beat fellow title rivals Tottenham 3-2 earlier.
"We said before the game that winning after City had won their game was the important thing," Ferguson said. "We did it in the right way, we played football and were adventurous and had belief in ourselves. I'm delighted with that at this time of the season.
"They are all important games, we have four massive away games and that is one out of the road."
Johan Djourou was given such a torrid time out of position at right-back by Nani that he had to be substituted for 18-year-old Nico Yennaris at half-time.
The Gunners have struggled to fill the spaces left vacant by their injured full-backs in recent weeks and Ferguson admitted he was conscious that area could be exposed.
"That's been their problem for a few weeks, that is a disappointment for them without natural full-backs like Bacary Sagna and Kieran Gibbs," Ferguson added.
"They are playing centre-backs there so it is difficult for them. But they had only conceded six goals at home until today so they have not done a lot wrong in the defensive part. We had to play well and for most of the game we did.
"It was an amazing amount of chances we had, it's always difficult coming to here and Arsenal are a top side.
"We're a bit disappointed that we only scored twice. The first half in particular was a golden period for us, we should have rammed home the advantage.
"Then in the first 15 minutes of the second half they had three great chances and missed them all, so we rode our luck there. But we hit on the counter attack and through the game we had great chances."
United's win came at a cost, however. Phil Jones was carried off on a stretcher after 15 minutes after turning his ankle, Nani hobbled off in the second half and left the stadium in a protective boot while Wayne Rooney was also hobbling at the final whistle.
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