Arsenal made six changes from their Europa League exit to Sporting as they looked to go eight points clear at the top of the Premier League.
Both Takehiro Tomiyasu and William Saliba missed out through injury as Ben White and Rob Holding came into defence.
Thomas Partey also came back into the side, as did Martin Odegaard, Leandro Trossard and Bukayo Saka.
Paddy McCarthy takes charge of Palace for the first time having temporarily taking the reins following the sacking of Patrick Vieira on Friday.
He made two changes as Luka Milivojevic returned as captain and Joel Ward was also recalled as Albert Sambi Lokonga missed out against his parent club.
After a slow start, the league leaders would break the deadlock through Gabriel Martinelli – the man whose saved penalty cost Arsenal in their shoot-out loss to Sporting.
Wilfried Zaha was caught ball-watching as White nipped in ahead of him, playing in Saka, whose cross was controlled and finished well by Martinelli.
Saka would double the lead before the break, finishing low past Joseph Whitworth having been played in by White.
Arsenal would pull further clear just before the hour, Granit Xhaka exchanging passes with Trossard before finishing under pressure from Ward.
Palace scored their first league goal in almost seven hours as Jeffrey Schlupp turned home from a corner to give McCarthy a glimmer of hope.
Saka’s second of the afternoon restored Arsenal’s three-goal lead as his fine first-time finish from Kieran Tierney’s cross survived a VAR check for offside.