Van Nistelrooy used his chest to control a lofted pass from Juan Sebastian Veron in the 60th minute before turning in one movement to hit a fierce right-foot volley past keeper Antonio Chimenti and into the roof of the net.
The Dutchman's third goal of the tour put United 3-0 up at the Giants Stadium on a night when Tim Howard, the U.S. international, made a confident debut in goal for Alex Ferguson's side.
With yellow cards for Paul Scholes and Roy Keane within two first-half minutes, United's commitment for the friendly was never in doubt.
They took a deserved lead after 24 minutes when Ryan Giggs, assuming set-piece duties following the sale of David Beckham to Real Madrid, stepped up to curl a direct free-kick into the corner of the net from 25 metres.
EXCELLENT INTERPLAY
Scholes doubled the advantage 12 minutes after halftime, sliding home a low shot after excellent interplay between Ole Gunnar Solskjaer and Veron, the Argentine again linked with a move to Chelsea this week.
The Italian champions made 10 outfield substitutions after 62 minutes and one of them -- Pavel Nedved -- reduced the deficit eight minutes later with a crisp drive from 20 metres.
It spoiled a perfect debut for Howard, who saved well from Alessandro Del Piero, David Trezeguet and Nicola Legrottalie.
United substitute Diego Forlan missed a clear opening moments later before making amends on 79 minutes with a cross-field pass for Solskjaer, who had time and space inside the area to beat Chimenti for United's fourth.
But that was as good as it got for Uruguayan Forlan. With Chimenti grounded a minute from time, the striker was left with an open goal but inexplicably shot wide from seven metres.
Forlan's personal nightmare could not spoil United's work. It was their third win in three tour matches, in front of a crowd of 79,005, a record for a soccer match at the Giants Stadium.
United face Barcelona in their final match in the U.S. on Sunday while Juventus meet AC Milan in the Italian Super Cup at the Giants Stadium the same day.
