Any slim hopes of a comeback, following last week's 6-2 defeat at Old Trafford, were perhaps dashed when Edinson Cavani opened the scoring at the Stadio Olimpico.
The Uruguayan striker would go on to score twice, just as he did in the first leg, but the Giallorossi overcame that thanks to goals from Edin Dzeko, Bryan Cristante and - on his senior debut - Nicola Zalewski.
The fact that Manchester United goalkeeper David De Gea was arguably Man of the Match should illustrate how many chances Paulo Fonseca's side created, and how they could have got even closer to an unforgettable comeback on another night.
In the end, however, they at least ensured that a memorable European run ended on a positive note - with plenty of credit to be taken from the overall performance.
ROMA 3-2 MANCHESTER UNITED (5-8 on agg.)
GOALSCORERS: Dzeko (57'), Cristante (60'), Zalewski (83'); Cavani (39', 68')
ROMA (4-2-3-1): Mirante; Karsdorp, Smalling (Darboe), Ibanez, Peres (Santon); Mancini, Cristante; Mkhitaryan, Pellegrini, Pedro (Zalewski); Dzeko (Mayoral)
Unused subs: Boer, Fuzato, Kumbulla, Bove, Ciervo
MANCHESTER UNITED (4-2-3-1): De Gea; Wan-Bissaka (Williams), Bailly, Maguire, Shaw (Telles); Van de Beek, Fred; Greenwood, Bruno Fernandes (Mata), Pogba; Cavani (Rashford)
Unused subs: Grant, Henderson, Lindelof, Diallo, Matic, Tuanzebe, McTominay, Elanga
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