Van der Sar was to blame for both of Pompey's goals while United found home goalkeeper David James at his inspired best as they slumped to a first league defeat since January.
Cristiano Ronaldo had the Pompey defence on the back foot early on when he raced past Dejan Stefanovic and Linvoy Primus, before shooting into the side-netting from the edge of the penalty area.
Portsmouth stunned the travelling United fans when they took the lead 15 minutes before half-time, with van der Sar at fault for the second time in four days.
The Dutchman only parried Benjani Mwaruwari's long-range shot, allowing Matt Taylor to slide in and place the rebound into the back of his net.
Michael Carrick should have equalised straight from the re-start when he latched on to Paul Scholes' defence-splitting past, only to shoot wide from close range with only James to beat.
James came to Pompey's rescue a few minutes later when he saved with the legs from point-blank range to deny Darren Fletcher an equaliser, after Carrick had opened up the defence.
James pulled off another breathtaking one-handed save to keep out Ronaldo's volley from a Ryan Giggs corner and Ole Gunnar Solskjaer's follow-up was cleared from the line by Lauren.
James needed to be at his brilliant best to turn Giggs' curling long-range shot over the bar soon after.
Van der Sar was at fault for Pompey's crucial second goal when he needlessly came racing off his line and allowed Rio Ferdinand's back pass to trickle past him for an own goal.
John O'Shea gave United hope when he tapped home a stoppage time consolation after James had spilled Solskjaer's shot.