After securing 12 points from a possible 18 during the group stages, Manchester United had been hoping to be handed an easier draw at the start of 2013 when the knockout rounds of the Champions League began in February.
However, after Real Madrid could only finish second in a group involving Borussia Dortmund and Manchester City, the two European giants were paired together in what would undoubtedly be two blockbuster clashes that would see one of the competition's major names exit the tournament before the last-eight stage.
The match also marked the first time that Cristiano Ronaldo had faced the Old Trafford outfit since his transfer to La Liga, and as expected, he was named in a strong attack that also included Mesut Ozil and Karim Benzema.
Manchester United boss Sir Alex Ferguson could have opted to name a defensive lineup for their fixture at the Bernabeu, but the Scot selected Danny Welbeck, Wayne Rooney and Robin van Persie in a team that he hoped would net an away goal before the second leg in England.
The home side started the match at a frantic pace, and after Sami Khedira and Angel di Maria had got early strikes in on goal, Ronaldo witnessed a curling effort tipped onto the post by a sprawling David de Gea.
The early pressure from Madrid continued until the 20th minute when Manchester United stunned the passionate home crowd by taking the lead. A free kick was swung over from the left by Rooney and Welbeck was on hand to take advantage of some hesitant defending to prod the ball into the net.
However, conceding a goal failed to change Madrid's mentality and after he had flashed another effort wide of the target, Ronaldo netted against his former club with a towering header from 12 yards out, but muted celebrations followed out of respect for the club that had given him the platform to develop into one of the world's best players.
The match was turning into an enthralling contest, with United's response almost seeing them regain the lead when Welbeck poked the ball towards goal from a Van Persie delivery, but Madrid stopper Diego Lopez just about managed to deal with the situation.
The English side began the second half on the front foot, but after a last-ditch intervention from Fabio Coentrao denied them a second goal, Madrid progressed up the other end when a quick turn and shot from Ronaldo was easily dealt with by De Gea.
The visitors were continuing to have their moments on the break, but they were beginning to come under fierce pressure from Los Blancos, who had Di Maria and Khedira make attempts to complete the turnaround without success.
Ferguson introduced Ryan Giggs to the action to try to calm things in midfield, but the veteran Welshman could do little to stem the pace of Madrid's attacks as they pressed relentlessly for a first-leg lead ahead of the second encounter in England.
However, the tide gradually began to turn and after hitting the post with a header, Van Persie wasted a glorious chance with 18 minutes remaining when he sliced the ball when put through on goal and Xabi Alonso was able to track back with time to spare to prevent the ball rolling into the net.
Back came Madrid, who sensed that their opponents would be happy with a draw, but United almost nicked victory in added-on time when Lopez was forced into a scintillating stop to tip Van Persie's volley away for a corner, but after the set piece came to nothing, the final whistle brought an end to a gripping match in Spain's capital.
The second leg saw United take control thanks to an own goal from Sergio Ramos, but the after the controversial dismissal of Nani, Madrid seized the advantage and a goal from Ronaldo proved to be the decisive goal.
United's early exit allowed them to easily seal the Premier League title during Ferguson's final campaign in charge, while the Spanish side missed out on a first European final since 2002 after they were stunned by Borussia Dortmund in the semi-finals.
