With 65 minutes on the clock, Dimitar Berbatov went through on goal, Van der Sar saved his initial effort but the ball landed at the striker's feet and his second attempt appeared to be blocked by Wes Brown's left arm, although replays proved inconclusive.
Ironically enough, it was at the same end of the ground that Pedro Mendes was denied a winning goal back in the 2004-05 season.
Moments earlier, Rio Ferdinand cleared off the line from Berbatov but it all counted for nothing when Nani pulled the trigger with 69 minutes on the clock and the ball arrowed into the top corner, clipping Carlos Tevez on the way.
Martin Jol was able to draft Berbatov back into attack alongside Robbie Keane in the absence of Darren Bent, who is struggling with a thigh problem. There was also a Premier League debut for Gareth Bale on the left flank, with Steed Malbranque switching to his more natural right sided territory.
Malbranque made an early impact last week against Derby and there was almost a quicker one this time as the Frenchman, via Berbatov, teed up Keane for a shot on goal, with the skipper curling a measured effort high beyond the reach of Edwin van der Sar that clipped the top of the crossbar.
Neither team really established a foothold in the game after the early possibility, with the contest becoming very chess-like in a vast arena with very little in the way of noise or atmosphere. A Nani cross that Ryan Giggs couldn't really latch on to provided a minor scare, but the chance at the other end from a Jermaine Jenas corner caused more than a spot of home concern due to Pascal Chimbonda making a decent connection and Anthony Gardner narrowly failing to slide in and convert at the far post.
On 15 minutes there was another opening from a Tom Huddlestone free-kick. Another Chimbonda header caused confusion that Keane was quick to pick up on and he laid the ball off for Ricardo Rocha in front of goal around 15 yards out, but the central defender blazed over.
United were rocking a little and Berbatov probably should have scored when he found himself through in the area following a spot of ball watching from Rio Ferdinand, but then United came to life and Paul Robinson had to be at his best to deny Ferdinand with a superb reaction save.
Paul Scholes was next in making an attempt to alter the scoreboard after being picked out by Carlos Tevez, with the former England man's clipped shot fizzing just over the bar. Nani later twisted and turned in the area before drilling a shot wide of Robinson's left-hand upright.
The tempo at the beginning of the second half was fairly sedate and the encounter remained cagey, with neither goalkeeper probably fearing the prospect of getting dirty. Huddlestone shot over in what was the first goal attempt of the half around five minutes in before Bale was crudely hacked down by Wes Brown in full flight on the counter attack.
Rocha should have scored when he planted his head on a precision free-kick from Bale on 55 minutes. He nodded wide, but the passage of play prompted United into change and Chris Eagles quickly replaced Michael Carrick afterwards.
The team in white and blue were definitely holding sway and you could almost feel the unease emanating from the home support.
It was nearly for very good reason on 63 minutes. Ferdinand gave the ball away to Bale and the young Welshman strode forward and prodded into the path of Berbatov, who appeared to be felled by Nemanja Vidic. Nothing doing according to referee Mr Webb, but the fallen Berbatov was also alert enough to stick out a leg and help the ball on towards goal, but Ferdinand scrambled clear off the line.
Berbatov was then on the charge again and was denied a clear penalty when Wes Brown used an arm to block his follow up after Van der Sar saved his initial effort. No was again the answer from the officials and frustrations mounted.
It almost seemed inevitable when Nani took aim and, from a deflection off Tevez, shot his team into the lead. An inevitable injustice perhaps.
Martin opted for double change with the introduction of both Jermain Defoe and Adel Taarabt for Lee Young-Pyo and Keane as the team set about attempting to right a couple of wrongs.
Berbatov came close to completing one with a quite brilliant attempt to find the top corner after spinning on the edge of the area but, again, it was a case of so near yet so far.
A key moment went against us again at Old Trafford as Nani's wonder strike won maximum points for Manchester United.