It is a first return for Smalling to the club for whom he made more than 300 appearances over a decade-long stint between 2010-20 and won a plethora of major silverware including two Premier League titles, the FA Cup, League Cup and 2017 Europa League before departing for Italy on an initial loan basis.
Smalling has successfully rebooted his career in Rome after falling down the defensive pecking order at United under Ole Gunnar Solskjaer and has returned from injury just in time for a reunion with his former club, having shaken off a knee problem to make his first start in a month in the 3-2 Serie A defeat by Cagliari on Sunday.
And the 31-year-old - whose home was recently targeted by armed robbers - admits Thursday is more than just any regular game for him.
"Yeah, 100 per cent [facing United brings extra motivation],” he said at a press conference appearance on Wednesday.
"It's a special game, it's a semi-final and added on top playing against United.
"Obviously being in Rome for nearly the last two years, I think, I know the importance of bringing home a trophy because it's been far too long.
"There's so many ingredients for this so I don't think there will be a bigger game to be a part of.
"I'm just thankful I'm now fit and I'm able to contribute because the whole squad needs every player."
On United’s progression under Solskjaer, who is desperately looking to avoid a fifth successive semi-final defeat and claim his first piece of major silverware as Red Devils boss, Smalling added: “This season they’re obviously having a very good season.
“When he first come in I was injured, but then as soon as I got fit he played me and we had a good relationship.
“Then obviously we had very honest conversations in the summer but, yeah, now we’ll meet on the pitch and I’m really looking forward to it.”
Additional reporting by the Press Association.