Chants of "You don't know what you're doing," rained down from the home crowd at the Emirates Stadium as well as a chorus of boos as the 18-year-old Oxlade- Chamberlain, who had just set up Van Persie's equalizing goal in the 71st minute, was replaced by the out-of-favor Russian.
Television cameras caught Van Persie shooting a curious glance at manager Arsene Wenger as he appeared to shout the word "no" in response to the switch.
It was a reaction that summed up the feeling inside the stadium as Wenger stood by and watched Arshavin easily beaten on the wing by United's Antonio Valencia in the build-up to Danny Welbeck's winning goal nine minutes from time.
The 2-1 loss was the third successive defeat suffered by the Gunners and leaves the club five points adrift of a place in the top four.
The result also spoiled a sparkling debut for Oxlade-Chamberlain, who was making his first career Premier League start and turned in a top-notch performance.
The 18-year-old was the most threatening player for Arsenal in attack as he showed the kind of pace and skill that made him such a highly-regarded prospect at Southampton.
Yet his debut ended about 20 minutes too early, leaving the blame squarely at the feet of the manager, who remained predictably defiant after the match.
"I can understand the fans are upset about the substitution, especially when it doesn't work," Wenger told The Daily Mirror. "It means I made the right decision at the start of the game (to play Oxlade-Chamberlain).
"He had started to fatigue. 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."
Sure Wenger deserves credit for handing Oxlade-Chamberlain a start in such a high-profile match, but to make the case that just because Arshavin is captain of Russia means that the substitution is warranted is ridiculous.
In truth, the Russian has expressed his desire to leave England and has looked generally disinterested while on the field, which again appeared to be the case on Sunday.
Wenger has done a lot of good at Arsenal since joining the club in 1996. However, he has come under increasing criticism over his reluctance to spend in the transfer window and the fact that the team has not won a trophy since the 2005 FA Cup.
The Frenchman has endured his fair share of unwarranted questioning in recent years, but it is becoming harder for him to put up a reasonable defense.
On Sunday, Arsenal started four central defenders across the back, which United exploited over and over again in the first half by repeatedly getting the ball wide to Nani in space.
Wenger corrected his error at halftime by taking off Johan Djourou in favor of a more natural full back in Nicholas Yennaris. Yet it was an issue that could have been avoided had the boss gone out and addressed the shortage in the transfer market instead of leaving his side thin at the position.
Stubbornness can be a virtue in certain situations, but Wenger's insistence on doing things his way has to be wearing thin with even his most ardent supporters.
"People pay their tickets and are free to express their emotions," Wenger said following Sunday's game. "We cannot dictate behavior to people. That doesn't mean they're right always.
"We lost the game just now and I do not have to explain to you what I do. I have to stand up to the result and the subs.
"I've been 30 years a manager and made 50,000 subs and I have to justify every decision I make to you? I stand up for it. I do not have to explain to you every single decision I make."
No, an explanation for every decision isn't required, but standing up and admitting when you're wrong every now and then wouldn't be a bad idea either.
Wenger has brought plenty of glory to Arsenal over the years, but his stubbornness is threatening to keep the club from adding any further accolades.