The teenage striker appeared as a substitute to score a stoppage-time victor against Hull before the worldwide break, before netting a hat-trick for England Under-21s.
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At the time, Mkhitaryan was expected to out of action for up to ten days, effectively ruling him out of the Manchester derby.
Henrikh Mkhitaryan and Jesse Lingard both come into the starting XI.
Marcus Rashford netted a hat trick for England under-21s in midweek but is not in the XI as Zlatan Ibrahimovic and Wayne Rooney start up front, with Anthony Martial and Juan Mata on the bench.
The £30million summer signing was injured on global duty in their 3-0 loss to Czech Republic and returned to England early in a bid to regain fitness.
Luke Shaw is fit to start after suffering a minor injury, while Antonio Valencia has returned in time form global duty to keep his place in the starting XI.
Claudo Bravo does make his City bow, with the former Barcelona goalkeeper replacing Willy Caballero between the sticks after his big-money summer move.
Mkhitaryan is yet to start a Premier League match for Man United.
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Claudio Bravo is handed a debut in goal.
