Hughes is accompanied by Cheikhou Kouyaté and Conor Gallagher in central midfield, with Jeffrey Schlupp dropping to the bench.
Joel Ward returns to the side in place of Nathaniel Clyne after being suspended for the trip to Old Trafford. James Tomkins and Marc Guéhi continue as the central defensive partnership, with Tyrick Mitchell completing the back-four.
In attack, Christian Benteke is replaced by Odsonne Edouard, alongside Jordan Ayew and Wilfried Zaha.
Eberechi Eze and Michael Olise are available as part of a strong Palace bench.
The visitors make three changes of their own after their victory over Arsenal on Monday night, with Fabian Delph, Mason Holgate and André Gomes replacing Allan, Yerry Mina and Anthony Gordon.
Former Eagle Andros Townsend starts in attack, alongside Richarlison.
Palace: Guaita (GK), Ward, Tomkins, Guéhi, Mitchell, Kouyaté, Hughes, Gallagher, Zaha, Edouard, Ayew.
Subs: Butland (GK), Olise, Eze, Mateta, Schlupp, Clyne, Benteke, Kelly.
Everton: Pickford (GK), Holgate, Keane, Richarlison, Delph, Gray, Townsend, Doucouré, Gomes, Godfrey, Coleman.
Subs: Begovic (GK), Kenny, Iwobi, Gordon, Gbamin, Brenthwaite, Rondon, Simms, Onyango.