Nemanja Vidic headed United level on the stroke of half-time after Nelson had given Benfica a 27th minute lead before Ryan Giggs and then Paul Scholes added second-half strikes to ensure Sir Alex Ferguson's side not only qualified for the last 16 but leapfrogged Celtic at the top of the group in the process.
Twelve months ago Benfica dumped United out of the competition following a 2-1 victory in Portugal and history looked like repeating itself as the home side laboured out of the starting gate at Old Trafford.
United were sluggish and sloppy in possession and were punished when dangerman Sabrosa Simao was allowed to run into acres of space down the right wing after 27 minutes.
The Portugal international waited patiently for support inside the box before playing the ball back to Nelson who lashed an unstoppable angled shot from 25 yards beyond Edwin Van der Sar.
The early setback seemed to rouse the home side and they had Vidic to thank for capping a spell of intense pressure with an equaliser on the stroke of half-time.
The Serbian defender shrugged off his marker and rose highest in the box to head home Ryan Giggs' inswinging free-kick to send the sides in level at half-time.
After the interval United stepped up their game and, after Louis Saha had lashed a 12-yard shot over the bar, they took the lead in the 61st minute.
Cristiano Ronaldo was given time on the right flank and he delivered a pinpoint cross for Giggs who had ghosted in unmarked to cushion home a simple header from close range.
Fifteen minutes from time - and with Benfica looking a beaten side - United added a third courtesy of Saha.
The France international pulled off the shoulder of his marker and met a corner with a close-range header that gave goalkeeper Quim no chance and ensured United swept into the knockout stages of the competition with relative ease.