Southampton 2 Manchester United 3
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The Dutchman needed just 23 minutes to add to his United tally and cancel out Rickie Lambert's opener.
But he was left red-faced after Morgan Schneiderlin had restored the lead for Nigel Adkins' newcomers.
Van Persie dusted himself down following an untidy challenge from Jos Hooiveld before seeing his attempt from the resulting spot-kick saved by Kelvin Davis.
The fact he missed was bad enough, but Fergie was left spitting feathers due to the manner in which the Arsenal legend tried and failed to mimic Andrea Pirlo's cheeky penalty style.
Van Persie eased the chances of a verbal blast at the final whistle by equalising three minutes from time after Rio Ferdinand thumped a header against the post.
And he broke Southampton hearts with his 100th Premier League goal deep into injury-time.
Heading into the game, much of the talk was about Fergusons decision to play Anders Lindegaard instead of regular keeper David de Gea.
Ferdinand was also a notable inclusion as he made his first appearance of the season, partnering Nemanja Vidic in defence for the first time since a 2-1 defeat to Basel last December.
The occasion seemed to get the better of the hosts in the opening exchanges and in the sixth minute Van Persie fired a volley just wide.
His attempt awoke Southampton up and they were soon pushing forward, with Adam Lallana shooting wide after meeting a clever low corner from Danny Fox.
Schneiderlin blazed over from long-range as the hosts continued to push for a goal that came after just 16 minutes.
Saints were getting a lot of joy down the right flank and made the most of it as Jason Puncheon sent a hanging cross to the back post, where Lambert headed home.
However, like so often against United, the goal only seemed to spur Fergusons side into life
Shinji Kagawa was first to show intent as he struck a speculative 20-yard effort that Davis pushed wide.
Southampton rode out that storm but could not prevent United drawing level.
Antonio Valencias cross from the right looked like it would be intercepted by Nathaniel Clyne but the Saints right-back slipped and Van Persie took full advantage.
RVP almost almost added another goal shortly afterwards with a nonchalant 20-yard free-kick which curled just wide.
It was not all United, though, as Lambert fired just wide and then both James Ward-Prowse and Lallana came close with long-range efforts.
But Fergusons side were proving adept at exploiting the hosts weaknesses
Fox was having a torrid time and it continued in the second half as Valencia beat him to a pass from Davis, although the Ecuadorians cross was not converted by Van Persie.
The domination counted for nothing, though, as another penalty-box slip resulted in a goal.
This time Ptrice Evra was the unfortunate party as his fall allowed Schneiderlin to nod home a Lambert cross.
The goal started a spell of dominance for the hosts as Jason Puncheon forced Lindegaard into a smart save at the near post, before Rafael cleared under pressure from Lambert and Lallana had an effort blocked.
Only Ferdinand prevented Ward-Prowse slotting home a Lambert cross, which was the signal for Fergie to send on Paul Scholes and Nani.
After Van Persie saw an effort saved by Davis, the Saints keeper sent a terrible miskick straight to Nani on the left.
The ball was worked into the box and Hooiveld upended Van Persie, who made it easy for Davis to push away his penalty.
Debutant Emmanuel Mayuka was among three changes by Adkins as he looked to close out the game under immense United pressure.
Javier Hernandez headed across the face of goal in the dying minutes and was then denied by a late Clyne tackle.
But the Saints could not stop United grabbing a later equaliser as Ferdinands header came back off the post and Van Persie directed home the rebound.
Things got even worse for the hosts in injury-time as the Dutchman nodded home Nanis cross to secure maximum points.
Southampton: Kelvin Davis, Clyne, Fonte, Hooiveld, Fox, Puncheon (Mayuka 74), Steven Davis, Schneiderlin, Ward-Prowse, Lallana (Rodriguez 78), Lambert (Do Prado 75). Subs not used: Gazzaniga, Lee, Richardson, Seaborne. Booked: Hooiveld.
Goals: Lambert 16, Schneiderlin 55.
Man Utd: Lindegaard, Rafael, Ferdinand, Vidic, Evra, Valencia, Cleverley (Scholes 61), Carrick, Welbeck (Hernandez 71), Van Persie, Kagawa (Nani 61). Subs not used: De Gea, Evans, Giggs, Powell.
Goals: Van Persie 23, 87, 90.
Att: 31,609
Ref: Mike Dean (Wirral)