The Belgian makes his first start since November 22 and only his second since the end of September as United look to finish off the job after their 0-0 draw in Seville three weeks ago.
Fellaini recently returned after knee surgery, coming on as a substitute in Saturday's 2-1 win over Liverpool, and replaces McTominay in the first XI for the Spaniards' visit.
However, there is no starting spot for Pogba, who suffered a gashed leg in training on Friday after a clash with McTominay and missed the clash with Liverpool as a result. He only took part in a portion of the team's training session on Monday as well, meaning a start was always unlikely.
Elsewhere there is one more change for Jose Mourinho's side, with Jesse Lingard coming in in place of Juan Mata. Mata drops to the bench to join the like of Pogba, McTominay and Anthony Martial, who returns after a muscle injury.
There is still no place for Zlatan Ibrahimovic despite his continued involvement in training, with Mourinho having confirmed recently that he is leaving the final decision over a return date down to the Swede himself as he looks to shake off the lingering effects of ACL damage.
A win of any description will take United through to the quarter-finals, while Sevilla know that a score draw will be enough for them to progress.
Man Utd: De Gea; Valencia, Smalling, Bailly, Young; Matic, Fellaini; Rashford, Alexis, Lingard; Lukaku.
Subs: Romero, Lindelof, Pogba, Mata, Darmian, McTominay, Martial.
Sevilla: Rico; Kjaer, Lenglet, Banega, Correa, N'Zonzi, Sarabia, Escudero, Muriel, Vazquez, Mercado.
Subs: Soria, Ben Yedder, Geis, Pareja, Noltio, Arana.