The Red Devils captain has missed the last two games with a wrist injury, but his return is the solitary change made to Erik ten Hag's starting lineup that began the 1-0 defeat at home to Arsenal last Sunday.
Fernandes is set to operate as a false nine as he has taken the place of striker Rasmus Hojlund, who drops down the substitutes' bench after 10 consecutive starts.
A back four or Aaron Wan-Bissaka, Casemiro, Jonny Evans and Diogo Dalot remains intact, although Man United have been boosted by the return of Lisandro Martinez to the matchday squad.
Sofyan Amrabat retains his place in centre-midfield alongside Kobbie Mainoo and Scott McTominay, while Fernandes will be supported in attack by wingers Amad Diallo and Alejandro Garnacho; Marcus Rashford, meanwhile, is fit to make the substitutes' bench.
As for Newcastle, Eddie Howe has also made just the one change to his side that drew 1-1 with Brighton & Hove Albion last weekend, with Kieran Trippier handed a start at right-back at the expense of Valentino Livramento, who misses out due to an ankle injury.
Trippier, starting his first game since early March, joins Emil Krafth, Dan Burn and Lewis Hall in the back four, while Fabian Schar is fit to make the substitutes' bench after missing the last two matches with a hamstring injury.
There are no changes to Newcastle's midfield, with Sean Longstaff, Bruno Guimaraes and Elliot Anderson all retaining their starting spots.
Star striker Alexander Isak emerged as a doubt in the build-up to tonight's fixture, but he has shaken off an illness to make the starting lineup and will be joined in a three-man frontline by Anthony Gordon and Jacob Murphy; Callum Wilson is not involved, however, as he has failed to recover from a minor hamstring issue.
Manchester United: Onana; Wan-Bissaka, Casemiro, Evans, Dalot; McTominay, Mainoo, Amrabat; Diallo, Fernandes, Garnacho
Subs: Bayindir, Kambwala, Martinez, Collyer, Eriksen, Antony, Forson, Hojlund, Rashford
Newcastle United: Dubravka; Trippier, Krafth, Burn, Hall; Longstaff, Guimaraes, Anderson; J. Murphy, Isak, Gordon
Subs: Pope, Dummett, Schar, Almiron, Joelinton, Barnes, Ritchie, A. Murphy, White