The Red Devils are close to securing the services of Ajax playmaker Donny van de Beek and Upamecano could now follow him to Old Trafford.
According to talkSPORT's transfer expert Alex Crook, United want to sell Smalling to Roma and Upamecano is their top defensive target.
"Manchester United are bracing themselves for a bid from Roma to keep Chris Smalling on a permanent deal," Crook told talkSPORT.
"He did brilliantly there on loan last season and even earned the nickname ‘Smaldini’ after the great Paolo Maldini – that’s some compliment!
"It’s talkSPORT’s understanding that Smalling would like to return to Italy. United are eyeing Dayot Upamecano from RB Leipzig, so his first-team chances at Old Trafford would appear to be limited.
"He had a pretty torrid time towards the end of his Old Trafford spell so I think it’s nice for Smalling to feel loved again.
"There was talk earlier in the summer that perhaps Solskjaer could give him a second chance and a chance to revive his Man United career, but they’re now in for Upamecano and the belief is that if someone is willing to pay money for Chris Smalling that would help fund their own transfer activities.
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"So this is one of those deals that would just make sense for all parties."
Van de Beek is believed to have agreed personal terms with the Red Devils and passed a medical, with the 23-year-old set to join for a fee of £40m.
Ajax boss Erik ten Hag has admitted that Van de Beek is likely to leave, saying: "We will see what happens.
"We’ll make an announcement as soon as there’s some clarity. The fact that Donny did not play does indicate a direction.
"The request not to let him play did not come specifically from one side. We do that together. Agreements have been made about a possible transfer, and if that possibility arises you must also cooperate."