The Armenian had been out of action for two weeks with a hamstring problem which caused him to miss two matches, including the EFL Cup final win over Southampton in February.
But after making a full recovery, he will look to make an impact for Jose Mourinho's men as they face a tough test on a difficult pitch in Russia.
Zlatan Ibrahimovic also starts, after seeing the FA hand down a three-match ban for domestic games following his elbow on Tyrone Mings. The striker hit a hat-trick in the last 32 to see off Saint-Etienne, and with five goals in the competition is tied in fourth in the top scorer rankings.
The inclusion of Phil Jones, Chris Smalling, Marcos Rojo and Daley Blind means that United could well play with a three-man central defensive unit for the first time this season, while Marouane Fellaini and Ander Herrera are back in the midfield and Sergio Romero has been recalled in goal for the rested David de Gea.
Rostov XI: Medvedev; Mevlja, Navas, Granat; Kalachev, Noboa, Gatskan, Erokhin, Kudryashov; Bukharov, Poloz. Subs: Goshev, Terentyev, Kireev, Bayramyan, Azmoun, Prepelita.
Man Utd XI: Romero; Young, Jones, Smalling, Rojo, Blind; Fellaini, Herrera, Pogba; Mkhitaryan; Ibrahimovic. Subs: De Gea, Valencia, Carrick, Lingard, Mata, Martial, Rashford.