Anthony Martial returns to the starting XI on the left, while Jesse Lingard steps in for his first league start of the season with Juan Mata likely to switch inside to replace Mkhitaryan as a No.10.
Phil Jones and Ashley Young both start in defence, with Daley Blind and Victor Lindelof replaced after playing the full 90 minutes in the 1-0 win over Benfica on Wednesday.
Huddersfield recall Aaron Mooy and give a second league start to Danny Williams as David Wagner bolsters his midfield against the second-placed Red Devils, while Chris Lowe returns at left-back in place of Scott Malone.
If United keep a clean sheet they will become the first Premier League team ever to shut out eight opponents in their first nine games of a season.
Huddersfield: Lossl; Smith, Jorgensen, Schindler, Lowe; Mooy, Williams, Hogg; Kachunga, Ince; Depoitre. Subs: Coleman, Malone, Sabiri, Cranie, Van La Parra, Mounie, Hadergjonaj.
Man Utd: De Gea; Valencia, Smalling, Jones, Young; Herrera, Matic; Lingard, Mata, Martial; Lukaku. Subs: Romero, Lindelof, Blind, Rashford, Mkhitaryan, Darmian, McTominay.