Wayne Rooney scored twice while Ji-Sung Park and Darren Fletcher were also on the scoresheet, although the Englishman's first goal only came after the Rossoneri had wasted two great early opportunities to get back into the tie.
United started the match as big favourites to progress after winning the first leg at the San Siro 3-2 and were able to welcome Rooney back into their starting line-up after the in-form striker has missed the 1-0 win at Wolves with a knee problem.
David Beckham, who was caught above his left eye by a boot kicked by a fuming Sir Alex Ferguson in a well-documented incident more than seven years ago, had to settle for a place on the Milan substitute's bench.
He did come on midway through the second half but by then the match was lost.
United started very brightly and almost took a third-minute lead when Rooney spun and sent a shot from the edge of the area just wide.
However, Milan hit back and six minutes later almost found a way back into the tie. Andrea Pirlo's free-kick was inadvertently headed on by Nani to Ronaldinho whose instinctive header was only just off target with Edwin van der Sar rooted to the spot.
In the 11th minute Milan created another great opening. Thiago Silva's long ball forward found Klaas-Jan Huntelaar but the Dutchman's first touch was poor and van der Sar was able to claim the ball.
They proved to be costly misses as United took the lead in the 13th minute when Gary Neville's superb cross found Rooney who was allowed to head powerfully past Christian Abbiati.
Seven minutes later Milan went close to pulling a goal back when Pirlo rifled a shot through a crowd of players that van der Sar eventually gathered at the second attempt.
There was a gulf in class between the two teams though with United in cruise-control for much of the first half as Milan bizarrely allowed them time and space in abundance.
United doubled their advantage on the night within 60 seconds of the restart. Nani played a sublime and precise ball to Rooney who nonchalantly clipped the ball over the advancing Abbiati and into the net.
Just before the hour mark it was 3-0 when a patient United build-up ended with Paul Scholes playing a simple pass in to Park who found the net with a low shot from a tight angle.
The match showed just how far Italian football has fallen in the last few years as Milan looked as though they would struggle to finish in the top half of the Premier League table on this showing.
Beckham did almost score a late consolation goal when van der Sar was forced to beat his fierce effort away but Darren Fletcher completed the rout with a late header that set the seal on an emphatic victory.