Only two teams have ever won a knockout tie in the competition after losing at home in the first leg and in both cases - Ajax Amsterdam against Panathinaikos in 1996 and Inter Milan against Bayern Munich in 2011 - they had only one goal to make up.
Although Tony Adams' side regrouped for the second half, the damage was already done and Real head into Wednesday's Champions League semi-final second leg with city rivals Atletico on the back of another impressive display.
The Real Madrid star is still on course to win another La Liga title and Champions League with decisive games coming up.
"It's very hard to overturn this result but we will keep believing until the end because that's our mentality and we will be playing with our fans behind us", Atletico defender Stefan Savic said.
Last Tuesday saw Real Madrid produce a convincing display and Cristiano Ronaldo score a hat-trick against an Atletico side that was nearly unrecognisable to the team that is usually so hard to beat, reports Xinhua news agency.
Life is good for Cristiano Ronaldo right now.
We have a final on Wednesday, three more in the league, but first we're going to focus on the game against Atletico Madrid.
It's win or stay home for good in Game 6
We were exhausted , our legs were exhausted , we were missing shots, we weren't playing with that zip like we normally play with". Bucks: Middleton made the only 3 of the first half for Milwaukee , which missed its eight other shots from behind the arc.
"It is a game where we have to give everything for the fans so that they can always be proud of their players", he said, quoted in Marca.
The match is being played at the Vicente Calderon. "We will try to do something impossible, but we are Atletico Madrid and we just might be able to do it".
"I've had to work there, pull people off, change people, plug holes, put (my) experience when kids are on the floor and you really have to work as a coach when the players are at another level to Real Madrid. The contrary, it is in our own hands", added the Spanish worldwide.
With less than 15 minutes to go Granada produced their best move of the night after some intricate football allowed Martin Hongla an attempt to add some respect into the scoreline, but the 19-year-old could only fire his effort over the top of the open goal - summing up the Nasrids' night and overall season.
Barcelona's 4-1 victory over Villarreal earlier on Saturday had left Real, who still have a game in hand, little margin for error.
Where else do you feel Real need to strengthen their squad?
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