De Gea drops to the bench for the first leg of the last-32 clash at Old Trafford, being replaced in the starting XI by Sergio Romero, while Mkhitaryan is left out of the matchday squad entirely due to illness.
Marouane Fellaini comes into the side in place of Mkhitaryan, while Bastian Schweinsteiger - who was added to the Europa League squad after missing out on a place in the group stages - is named on the bench.
Captain Wayne Rooney and Michael Carrick miss out due to muscular problems, while Phil Jones is sidelined with a foot injury and Luke Shaw is left out of the matchday squad for a fourth consecutive game.
Zlatan Ibrahimovic will lead the line having scored 14 goals against Saint-Etienne during his time with Paris Saint-Germain - more than he has managed against any other opponent during his career.
Saint-Etienne, who are making their first ever trip to Old Trafford, include three players with Premier League experience in their side, with Kevin Theophile-Catherine, Jordan Veretout and Henri Saivet having played a season each at Cardiff City, Aston Villa and Newcastle United respectively.
Manchester United: Romero; Valencia, Bailly, Smalling, Blind; Fellaini, Herrera, Mata, Pogba, Martial; Ibrahimovic
Subs: De Gea, Darmian, Rojo, Schweinsteiger, Lingard, Young, Rashford
Saint-Etienne: Ruffier; Malcuit, Theophile-Catherine, Perrin, Pogba; Jorginho, Veretout, Pajot, Saivet; Hamouma, Monnet-Paquet
Subs: Moulin, Selnaes, Lacroix, Roux, Lemoine, Pierre-Gabriel, Beric
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