The second leg of the last-16 encounter turned firmly in the favour of the side from Spain the moment referee Cuneyt Cakir brandished a shock red card to Nani in the 56th minute following the winger's clumsy, but not malicious, high challenge on Alvaro Arbeloa.
United had edged ahead on aggregate shortly after the interval as Sergio Ramos could only divert Nani's drilled low cross into his own net after it had flicked off the foot of Danny Welbeck, with Sir Alex Ferguson's side in the ascendency at that point.
But Nani's dismissal sparked a spell of Real pressure which United could not withstand, as substitute Luka Modric, sent on for Arbeloa, curled home a delicious strike from the edge of the box in the 66th minute.
And, somewhat inevitably, it was former Manchester United favourite Ronaldo who had the final say, sliding in at the far post to convert Gonzalo Higuain's drilled cross-shot after the striker's mesmerising one-two with Mesut Ozil.
Ferguson sprang a major surprise with his team selection, leaving Wayne Rooney on the bench and tasking Welbeck with nullifying the threat of Xabi Alonso, a job he performed excellently, particularly in the opening 45 minutes, until Nani's exit left United a man down.
Ryan Giggs was named in the starting XI for his 1,000th senior career appearance and lined up in an unfamiliar role on the right of midfield, providing additional protection to full-back Rafael against the danger posed by Ronaldo on his first appearance back at Old Trafford.
United came closest to breaking the deadlock in the opening period, when Giggs' fine corner from the right was met with a thumping header by Nemanja Vidic which crashed back off the upright before striking Welbeck and then landing between Diego Lopez's legs.
Ferguson stressed the importance of his side taking their chances at the interval and they responded immediately as Giggs and Rafael combined down the right, before Welbeck and Van Persie were kept out, only for Nani to pick Raphael Varane's pocket and force Ramos to put through his own net.
But the Portuguese winger's dismissal left United under the cosh and, despite the impassioned urgings of Ferguson and Giggs to stir the home crowd, Modric and Ronaldo both found a way beyond the excellent David De Gea in the space of four minutes to crush their hopes.
To their credit, United were not bowed and created several chances to get back into the contest, with Lopez saving superbly from headers by Michael Carrick and Nemanja Vidic, while Rooney, who was eventually thrown on in the 73rd minute, blasting over when well placed.
But Real could have extended their advantage, with Ronaldo drawing two further excellent saves from De Gea, while Kaka's deflected shot from a tight angle on the left of the area struck the goalkeeper's near post and then his back, before the shot-stopper gratefully gathered on his own line.