We look at five standout matches between the clubs.
Crystal Palace 2 Southampton 2 (Premier League, May 2005)
A classic relegation six-pointer ended in a tetchy draw in the penultimate game of the season that did little to help either side's hopes of staying up.
Palace were poised to climb out of the drop zone as they led 2-1 through goals by Fitz Hall and Nicola Ventola but Danny Higginbotham stabbed in a 90th-minute leveller.
Gonzalo Sorondo for Palace and Southampton's Peter Crouch, who had scored his side's first equaliser from the penalty spot, were both sent off after a melee.
Palace lost to Charlton a week later and ended up being relegated by a point after West Bromwich Albion produced a remarkable late escape. Southampton finished bottom.
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Southampton 2 Crystal Palace 0 (FA Cup semi-final 1976)
Second-tier Southampton reached the FA Cup final for the first time in 74 years as they beat Malcolm Allison's third-tier Palace with goals by Paul Gilchrist and David Peach.
An edgy game at Stamford Bridge came alive late on as Gilchrist fired Saints ahead before Mick Channon was brought down in the box and Peach converted from the spot.
Lawrie McMenemy's Southampton went on to win the competition for the only time in their history, stunning Manchester United in the final.
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Southampton 1 Crystal Palace 0 (second division, April 1966)
Norman Dean scored the winning goal as Southampton continued their pursuit of promotion to the top flight of English football for the first time. The Southampton team also contained a teenaged striker in Channon who went on to become one of the club's all-time greats, scoring 228 goals.
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Southampton 6 Crystal Palace 0 (First division, May 1971 )
The final game of an impressive season for Ted Bates's Southampton resulted in a thrashing of Palace as they celebrated qualifying for the UEFA Cup.
Jimmy Gabriel, Les Harfield and Ron Davies scored before the break and Channon struck twice after it, his second an unstoppable free kick. No game between the sides has ever been won by such a wide margin.
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Crystal Palace 3 Southampton 0 (Premier League, Dec 2016)
With Palace manager Alan Pardew under pressure of the sack birthday boy Christian Benteke scored twice to buy him some time. It ended a run of six straight defeats for Palace for whom James Tomkins was also on target.
Time ran out for Pardew 20 days later, though, when he was sacked and eventually replaced by Sam Allardyce.
(Reporting by Martyn Herman, editing by Ed Osmond)
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