A FIRST-HALF strike from Wilfried Zaha was enough to condemn Saints to an opening-day defeat at Selhurst Park.
Saints, who have not won their first Premier League match of a season for seven years, fell behind in the 13th minute thanks to Zaha's smart finish.
And despite Che Adams, Nathan Redmond and Danny Ings all going close, Crystal Palace held on to claim a 1-0 win.
Ralph Hasenhuttl made just two changes from the side which started the final game of the 2019-20 season, less than seven weeks ago.
One was enforced with the injured Stuart Armstrong replaced by Will Smallbone, for just his fifth Premier League start. The other change saw Jack Stephens partner Jan Bednarek in the heart of the defence, with Jannik Vestergaard dropping to the bench. He was joined among the substitutes by goalkeeper Fraser Forster following his loan spell at Celtic, with Angus Gunn missing out.
Crystal Palace named new signings Eberechi Eze and Michy Batshuayi among their substitutes, with young defender Tyrick Mitchell making just a third Premier League start.
Saints got off to a bright start, testing goalkeeper Vicente Guaita as early as the fourth minute, when defender Stephens saw his low header held after meeting a James Ward-Prowse corner.
Che Adams and Danny Ings then linked up, with the latter just unable to nip in ahead of Guaita.
But it was Palace who took the lead with their first meaningful effort on goal. Saints lost possession in midfield, allowing Andros Townsend to break down the right. His cross was perfectly weighted to the back post, where an unmarked Zaha was on hand to volley home with his right foot.
That seemed to knock the early stuffing out of Saints, with boss Hasenhuttl barking at his players to up the tempo in their attacks.
Palace rarely threatened for the remainder of the half either, other than via set pieces, but they went in at the break 1-0 up.
Hasenhuttl made a switch at the break, introducing Vestergaard in place of Bednarek at the back.
And Saints almost made an instant response after the restart. After working the ball well around the box, it fell to Redmond, whose effort was stopped by Guaita.
But disaster looked to have struck again just a few minutes later. Kyle Walker-Peters, making his first appearance since signing permanently for the club, was shown a straight red card for catching Mitchell with a high boot. However, after consulting with VAR Craig Pawson and the pitchside monitor, referee Jon Moss overturned his decision and downgraded the punishment to a booking.
Saints continued to press forwards and looked certain to equalise when Adams found space in the box, but his effort was superbly swatted away down low by Guaita.
Redmond was the next to try his luck on the left, but shanked off target as the visitors built up a head of steam.
Ward-Prowse fired a free-kick just over the crossbar as the game ticked towards its final 15 minutes, before Hasenhuttl turned to his bench to introduce Moussa Djenepo, in place of Smallbone.
But it was Palace who had the ball in the net again when Zaha burst clear and tucked into the bottom corner, but VAR decided to rule the effort out for offside.
Hasenhuttl's last throw of the dice was to introduce Shane Long in place of Adams.
And Saints almost snatched a point at the death. Walker-Peters's first-time cross from the right was met powerfully by Ings, but his header was parried away by Guaita.
Saints: McCarthy, Walker-Peters, Stephens, Bednarek (Vestergaard, h-t), Bertrand, Romeu, Ward-Prowse, Smallbone (Djenepo, 77), Redmond, Adams (Long, 85), Ings.
Unused subs: Vokins, Tella, Obafemi, Forster (g/k).
Booked: Walker-Peters.
Crystal Palace: Guaita, Ward, Dann, Kouyate, Mitchell, Townsend, McArthur, McCarthy (Milivojevic, 74), Schlupp (Eze, 81), Zaha, Ayew.
Unused subs: Kelly, Woods, Meyer, Batshuayi, Hennessey (g/k).
Booked: Schlupp.
Referee: Jon Moss.
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