Sergio Ramos' own goal gave United the lead on the night, but the sending off of Nani, after a high challenge on Avaro Arbeloa, swung the contest.
Substitute Luka Modric scored within seven minutes of his introduction, after evading Michael Carrick, before Ronaldo provided the crucial intervention, tapping home after Gonzalo Higuain's cross.
While Jose Mourinho's hopes of winning a third European Cup with a record third different club remains alive, the game with most likely be remembered for referee Cuneyt Cakir's decision to send off Nani with United ahead on aggregate.
Rarely had a Champions League tie been accompanied by more subtext, with Ronaldo returning to United for the first time since his departure in 2009, Ryan Giggs making his 1000th professional appearance and Mourinho doing battle once again with old advisary Sir Alex Ferguson in a meeting between unquestionably two of the world's biggest clubs.
But in a game of such enormity between these two world giants, both sides opted to leave out crucial components to their make-up, with Karim Benzema, and perhaps more surprisingly, Wayne Rooney, omitted from the start.
With Iker Casillas remaining unavailable with a broken finger despite travelling to Manchester, Madrid made just one change from the first leg, while United made three in all, with Nani and Tom Cleverley both earning starts.
While in the early moments at the Bernabeu it was United who went on the offensive, the opening exchanges of the second leg saw Madrid take the initiative, Higuain manufacturing the first chance, but only curling wide.
The hosts, following a nervy opening, quickly came into their own and should have taken the lead on the night as Nemanja Vidic's header thundered against the post, but when the rebound fell the way of Danny Welbeck, the England international's instinctive finish was gathered by Diego Lopez.
In their pass masters Xabi Alonso and Sami Khedira Madrid were seemingly content to play keep ball in the United half, as Welbeck and Nani were used as the out-ball for the Premier League leaders.
However, as the game reached the half hour mark, chances came with more regularity at both ends as the pair's attacking tendencies came to the fore with David de Gea alert to deny Higuain from a tight angle and Lopez blocking Welbeck's dinked effort after Van Persie had stung the Spaniard's palms.
There were no changes at the interval from either side, but within three minutes the deadlock was broken as first Welbeck and then Van Persie were denied before Ramos stabbed into his own net from Nani's follow-up cross.
But that turned out to be the Portuguese winger's final involvement as a high challenge on Arbeloa resulted in Turkish referee Cakir showing a red card to Nani, a moment which sparked a turnaround in the tie.
United had over half an hour to hold out but with 24 minutes left substitute Modric thumped home from 30 yards beyond a desparing De Gea.
And the tie was turned on its head a minute later as Ronaldo met Higuain's driven effort across goal at the back post, sliding the ball into an unguarded net to add to compound the injustice of Nani's earlier red card.
With a two-goal cushion in the tie Madrid replaced Mesut Ozil with Pepe for the final quarter, attempting to restrict space in a United attack bolstered by the introduction of Rooney.
Chances came for United in the final moments however, Van Persie twice being denied by Lopez, the first from a bullet header, the second a dinked shot after Rooney's pass before the 27 year old himself volleyed over from six yards.
Captain Vidic should have halved the required score in the first of five added on minutes, but Lopez pushed away his header, and Madrid were able to see out the remainder, to reach the quarter final and end United's hopes of a second treble.
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