Needing to defeat Sporting Lisbon to ensure qualification to the knockout stages as the top seeds in Group F, United boss Sir Alex Ferguson had named a strong looking line-up.
However, a spirited Sporting side made life hard for United, who fell behind to a 21st minute Fernando Abel opener, before clawing their way back into the match with an improved second-half showing.
Ronaldo then stepped up to the plate with a superb 25-yard free-kick in stoppage time to ensure the Red Devils maintained their 100 per cent Champions League record.
The result also means Ferguson can rest players in their final match against AS Roma next month in a match which comes just five days before a Premier League showdown with biter rivals Liverpool.
Ronaldo and Nemanja Vidic both returned to the starting line-up after missing the weekend defeat to Bolton Wanderers
Anderson, Darren Fletcher, John O'Shea and Tomasz Kuszczak were also handed starts in a much changed line-up.
But in the opening stages the home side struggled to find much fluency to their attacking play and only an eight-yard shot dragged wide by Louis Saha when a delightful Ronaldo flick had opened up the defence threatened the Sporting goal.
With United surprisingly off the pace, the visitors took full advantage when they claimed a 21st minute lead.
Full-back Abel smashed over a low cross from the right wing which crept between Kuszczak and his near post much to the keeper's embarrassment.
United sent on Carlos Tevez and Ryan Giggs at half-time and the double change had the desired effect as the home side visibly upped their game in the early stages of the second period.
Ronaldo went close with a 51st minute header from a Giggs free-kick before Saha dallied on the ball when put clean through by the Portuguese winger and was crowded out when poised to pull the trigger.
United were building a head of steam and they finally got themselves back on level terms on the hour-mark.
Patrice Evra's driven cross was played into the path of Ronaldo by Saha and his low shot was turned into the net by Tevez in the six-yard box.
After that it was all one-way traffic with United sensing the visitors were there for the taking but unable to find enough quality to open them up for a second time.
However with a draw on the cards, Liedson gave away a needless free-kick for a foul on Anderson in stoppage time and Ronaldo struck a hammer blow with a dipping shot from 25 yards which illuminated an otherwise disappointing European night at Old Trafford.