The Seagulls were in the ascendancy early doors and went into half time 2-0 up courtesy of goals from ex-Saint Adam Lallana and an own goal from Romain Perraud.
A Solly March stunner made it three for the visitors in the second half before James Ward-Prowse gave Southampton a glimmer of hope, but Brighton were otherwise untroubled as the Saints dropped to the bottom of the table.
Roberto De Zerbi had warned Southampton to expect an "angry" Brighton following their EFL Cup elimination at the hands of League One outfit Charlton Athletic, but it was the home side who enjoyed the better of the early exchanges chance-wise, with the Seagulls taking a bit of time to stamp out defensive wobbles.
However, Gavin Bazunu then failed to cover himself in glory as the Seagulls took the lead in the 14th minute, as Solly March crossed for ex-Saints midfielder Lallana to steer a header towards goal, which went through Bazunu's hands into the back of the net.
The St Mary's crowd welcomed the sight of Ward-Prowse standing over a free kick in a promising position in the 29th minute, but the set-piece specialist's effort flashed just wide of the post.
Any fleeting hopes of a first-half response from Southampton were seemingly extinguished in the 35th minute, as Perraud diverted Pervis Estupinan's cross from the left into his own net under pressure from March.
Joe Aribo and Stuart Armstrong were both brought on to cheers from the Southampton fans at half time, but it was the Brighton contingent whose jubilation was reignited just 10 minutes into the second half.
March - who set up the first goal and had a major part to play in the second - cut inside from the right before letting fly from a good 20 yards, and his tremendous strike found the top corner to put the Seagulls out of sight.
However, Southampton would be handed a route back into the game when Sam Edozie was clattered by Pascal Gross inside the area; Robert Sanchez managed to save Ward-Prowse's penalty, but the Saints captain headed in the rebound in the 73rd minute, but his effort could not spark an improbable late turnaround.
Wolverhampton Wanderers' win over Everton means that Southampton now sit 20th ahead of their New Year's Eve clash with Fulham, while Brighton have temporarily risen above Liverpool into sixth before they meet Arsenal this weekend.