The England international has only scored once for the Red Devils this season, and he is one of a number of players to drop out following the 3-0 loss to Manchester City at the weekend.
Alejandro Garnacho gets the nod on the left, while there is a start through the middle for Anthony Martial, with Rasmus Hojlund also named among the substitutes.
In total, Man United head coach Erik ten Hag has made seven changes from the Manchester derby, with Hannibal Mejbri and Mason Mount also coming in.
Casemiro has also returned, with the experienced midfielder overcoming the problem which he picked up while representing Brazil during the international break.
Newcastle's team, meanwhile, shows eight changes from the side that started the 2-2 draw with Wolverhampton Wanderers last time out.
Sean Longstaff captains the team on his 150th appearance for the Magpies, while there are spots on the bench for youngsters Ben Parkinson and Amadou Diallo.
Joelinton will seemingly lead the line for Eddie Howe's side, while Lewis Hall, Matt Ritchie and Tino Livramento are also among those to earn starts at Old Trafford.
Manchester United: Onana; Dalot, Maguire, Lindelof, Reguilon; Casemiro, Hannibal; Antony, Mount, Garnacho; Martial
Subs: Bayindir, Amrabat, Fernandes, Rashford, Hojlund, Eriksen, Wan-Bissaka, Evans, McTominay
Newcastle United: Dubravka; Livramento, Krafth, Dummett, Targett; Hall, Longstaff, Willock; Ritchie, Joelinton, Gordon
Subs: Karius, Trippier, Lascelles, Wilson, Almiron, Burn, Guimaraes, Diallo, Parkinson
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