United defender Rio Ferdinand had the first real chance of the match when he hit a good shot which was parried by Benfica keeper Joaoquim Quim after ten minutes of play.
But it was Benfica, who needed to win the match to progress to the knockout stage, who drew first blood after United's early pressure.
Energetic midfielder Simao found his way into the United box, drawing the attention of Vidic, Patrice Evra and Saha, thus leaving his teammate Nelson unmarked just outside the box.
The right fullback hit an absolute screamer from Simao's pass, hammering his shot into the top corner of the net giving a diving Edwin Van der Sar no chance and sending Benfica to the lead in the 27th minute.
The opening goal sparked a period of fast-paced entertaining football with United looking for an equaliser, and it wasn't long before Ronaldo had a swerving free kick tipped over the bar by Quim.
United provided a thrilling end to the half for their home crowd as they put sustained pressure on the Benfica goal.
The comeback begins
The pressure paid off on the stroke of halftime with Giggs swinging in a free-kick from the left to find the towering Vidic losing his marker Nuno Gomes before rising and powering a header home past Quim.
All of a sudden the tone of the match had changed, and United wnet for the kill in the second half.
In the 61st minute Ronaldo's deft cross from the right found Giggs' ghosting run in between the Benfica defenders, catching them unawares and heading home neatly unchallenged.
Benfica then needed two goals to go through to the knockout stage and it was Simao who sparked the Portuguese side with some incisive runs into the box.
But United would be the ones to go through after Saha shrugged off Nelson's shirt pulling to head home solidly from substitute Darren Fletcher’s corner in the 75th minute.
Red Devil's coach Sir Alex Ferguson would have been nervous at 1-0 down, but his team showed true spirit and some excellent skill to fight back and win impressively.
Other Wednesday action
In the other Group F fixture, FC Copenhagen defeated Celtic 3-1 in Denmark with first half goals to Atiba Hutchinson and Jesper Grönkjaer and a second half strike to Marcus Allbäck, however the Scottish champions had already qualified for the next round and got a consolation goal through midfielder Jirí Jarosik.
Group E was a forgone conclusion before the final round of matches, with Lyon and Real Madrid already qualified for the round of 16, Steaua Bucharest into the UEFA Cup and the winless Dynamo Kiev out of the European competitions.
Nevertheless, Kiev managed to draw with Real 2-2 in the Ukraine with a first half double to striker Maksim Shatskikh for Kiev cancelled out by a second half double to Ronaldo for Real.
Steaua drew 1-1 with Lyon away in France, with midfielder Nicolae Dica scoring after just two minutes for the visitors, while Alou Diarra equalised for Lyon.
In Group G Porto took on Arsenal with both sides only needing a draw to progress, and not surprisingly a 0-0 stalemate ensued in Portugal, while Hamburg came from behind to defeat CSKA Moscow in a 3-2 thriller in Germany, although CSKA still qualified for the Uefa Cup.
Finally in Group H, AC Milan were already assured of topping their group and therefore probably didn't mind getting beaten 2-0 at home by French side Lille with goals from Peter Odemwingie and Abdul Kader Keita.
Anderlecht and AEK Athens played out a 2-2 draw in Belgium, but Lille's surprise win at the San Siro saw them take second place in the group with AEK having to settle for the Uefa Cup.
The draw for the first knockout stage of the Uefa Champions League takes place on December 15 in Nyon.