The tie will take place on the weekend of 7th-8th January 2023, with kick-off time and broadcast details to be announced in due course.
The Eagles are looking to go one better than last season when they reached the semi-finals at Wembley, ultimately losing out to Chelsea.
Palace last faced Southampton in October, when Odsonne Edouard scored the only goal in a 1-0 win. Saints currently sit 19th in the Premier League.
Stay tuned on cpfc.co.uk, the official app and across our social media channels for confirmed ticketing details for this opening FA Cup clash.