Smalling, 29, has welcomed the prospect of facing the five-time Ballon d'Or winner for the first time in a competitive fixture despite the Argentine being the highest scorer in Europe's top five leagues this season with 43 goals and 21 assists in 40 games across all competitions.
"It's something to relish, I think," Smalling told the club's official website. "This season I've been lucky enough to face Ronaldo and Mbappe and they're all challenges that I definitely relish and I think players at this club relish.
"I say bring it on."
The former 31-time capped England defender also claimed the draw with Barca holds no fear for United, who overturned a 2-0 first-leg deficit against Paris Saint-Germain to reach the quarter-final of Europe's elite club competition.
"We showed as a collective the work we have done can result in a performance against the best team in the world.
"When we saw it was Barcelona in the draw we were smiling because it was another challenge and we will go head on," Smalling added.
"You work so hard to be in the Champions League places, these are the ties you look forward to. All the hard work in the group stages comes to this."
United and Barca kickoff at Old Trafford tonight at 21:00 (SAST)