The last-16 first-leg clash in the Bernabeu will pit the Portuguese goal-machine up against United for the first time since leaving for a world record fee of £80 million in 2009.
Ronaldo has fully justified that huge fee, scoring 182 goals in 179 appearances for the Spanish giants and a hat-trick against Sevilla at the weekend underlined the danger he poses to United's hopes of progress.
Yet Neville, who watched Ronaldo develop into one of the world's leading players at Old Trafford after he joined from Sporting Lisbon, thinks the flamboyant 28-year-old could try to hard to impress.
"I always think there's a weakness in everybody," former United defender Neville, now working as a Sky Sports analyst and as part of England's coaching set-up, said in the Daily Telegraph on Tuesday.
"You just wonder whether this match emotionally might be difficult for him, seeing all those lads he had such great times with still playing - Rio (Ferdinand), (Patrice) Evra, (Wayne) Rooney and Ryan (Giggs).
"You're always challenged in football and that will be a new experience for him.
"Maybe the emotion of seeing Sir Alex Ferguson, the red shirt, that stadium, we won't know how he'll deal with it, until we see him do it. It's new for him."
Ronaldo's final game for United was the Champions League final defeat by Barcelona in 2009 when he was not at his best - but he was generally prolific at Old Trafford with 118 goals in 292 games.
He helped the club to a stash of silverware, including three Premier League titles and the 2008 Champions League when he scored in the final against Chelsea.
"We are going to have to use all of our courage, ability and experience to make sure we not only stop Ronaldo, but the other players they have because Real are a great team," Ferdinand said.
"It's going to be an emotional night for Ronaldo, and a great night for him. Hopefully it gets too emotional for him."
Whatever happens over the two legs, Neville says Ronaldo will forever be remembered as one of United's best players - possibly the best of all time.
"People talk about Duncan Edwards, George Best and other exceptional talents but can there really have been anyone at Old Trafford who influenced matches like we saw him do between 2006-08," he said.
"That was the time when we were in the dressing room thinking, if we can keep a clean sheet, he can go out and win it for us. For me, you define greatness by whether you have an influence over the biggest matches. He did continuously."