Smalling, who only returned from a knee injury against Cagliari last week, made more than 300 appearances for United across almost a decade before initially joining Roma on loan in 2019 – a deal that became permanent the following year.
A two-time Premier League winner with United, Smalling will line up against his former team-mates in the opening leg of the final-four showdown at Old Trafford.
"It's a special game, it's a semi-final, added on top it's playing against United," he said. "Being in Rome for nearly the last two years I know the importance of bringing home a trophy because it's been far too long.
"There are so many ingredients that I don't think there'll be a bigger game to be a part of. I'm just thankful that I'm now fit and I'm able to contribute because the whole squad needs every player."
Smalling's reunion at Old Trafford will be played without fans due to COVID-19 restrictions.
"I'd admit that's one disappointment not to have a full house and likewise to even have my friends and family watching two clubs that have been a big part of my career," Smalling said.
"That's one unfortunate thing but it doesn't take away the emotion side because it's very rare when you go onto a pitch and you know every player on the pitch.
"In such a big game as well, I think it's got all the ingredients to put on one of your best performances."
Smalling's United exit came during the early stages of Ole Gunnar Solskjaer's tenure as he moved to the Italian capital on loan two years ago.
The 31 year-old said he had nothing against the Norwegian manager about his departure.
"When [Solskjaer] first came in I was injured but when I got fit he played me and we had a good relationship," Smalling said. "We had very honest conversations in the summer but now we'll meet on the pitch and I'm really looking forward to it."
Smalling missed six weeks with the knee injury that he only returned from against Cagliari on Sunday.
"Personally I'm feeling good," he said. "It's no secret that I have missed a lot of games this season which is very unusual for me.
"But coming into this game I'm feeling fit. I'm feeling ready to contribute."
Roma will be looking for its first European victory away to English opponents since February 2001 (1-0 against Liverpool in the UEFA Cup), having failed to win in its last 12 such games against seven different English sides.
Roma has lost all three of its previous away games against United, conceding nine goals and scoring just once in return. This will be its first such trip since April 2008, when it lost 1-0 in a Champions League quarter-final.