Hughes comes into the side in place of Jeffrey Schlupp in midfield, with Edouard - whose last start was a match-winning turn against the same opposition - introduced for Ebere Eze.
Both Schlupp and Eze are named among the substitutes, while defender Tyrick Mitchell remains unavailable following his recent red card against Fulham.
As a result, an anticipated back four will comprise full-backs Nathaniel Clyne and Joel Ward and centre-backs Joachim Andersen and Marc Guéhi, protecting goalkeeper Vicente Guaita.
Hughes and Cheick Doucoure are expected to anchor the midfield ahead of them, behind an expected attack of Wilfried Zaha, Michael Olise, Jordan Ayew and Edouard.
Palace: Guaita (GK), Clyne, Guéhi, Andersen, Ward, Doucouré, Hughes, Olise, Edouard, Zaha, Ayew.
Subs: Johnstone (GK), Milivojevic, Tomkins, Eze, Mateta, Schlupp, Richards, Riedewald, Gordon.
Southampton: Bazunu (GK), Maitland-Niles, Lyanco, Caleta-Car, Aribo, Ward-Prowse, A. Armstrong, Adams, Perraud, Salisu, Edozie.
Subs: Caballero (GK), Walker-Peters, Mara, Djenepo, Elyounoussi, Diallo, Lavia, Morgan, Finnigan.