It seemed United were again set to drop vital home points - this time in group D of the Champions League - before the Dutchman's 43rd European goal.
With United again struggling to break down opponents, United won a corner on the right in the 85th minute.
Ryan Giggs, scorer of their first goal, curled the ball in to the near post where Rio Ferdinand rose to get in a header ten yards out.
The ball took a deflection off Nelson and landed perfectly for van Nistelrooy to hook in his right-foot shot from close range.
United had taken a 39th minute lead following Leo's foul on Cristiano Ronaldo four yards to the right of the Benfica penalty area.
Giggs, captaining the Red Devils on his 100th European appearance for them, curled the resulting free-kick into the far corner of the net, courtesy of a major deflection off Simao.
But Simao more than made up for his part in it when he equalised with a glorious 59th minute shot.
Alan Smith brought down Fabrizio Miccoli 25 yards to the left of the United box and Simao bent his superb right-foot free-kick beyond goalkeeper Edwin Van der Sar and into the roof of the net.
United's best chance of the game before the Giggs goal came in the 14th minute.
Phil Bardsley's cross from the right was beautifully controlled by van Nistelrooy who showed amazing skill to drag the ball back before hitting a stunning left-wing shot which crashed against the Benfica bar.
Benfica had their chances and Van der Sar was twice forced to make good saves.
The first came in the eight minute when he dived across his line to push away Ricardo Rocha's close-range header from Manuel Fernandes' corner.
The second came when he beat out Simao's 25-yard shot after 67 minutes.