Watford were relegated after a 1-0 loss at Crystal Palace, while Burnley suffered a 3-1 defeat at home to Aston Villa.
The Eagles had star forward Wilfried Zaha to thank for the three points as the Ivory Coast international converted a spot-kick midway through the first half to seal the Hornets' fate.
Their task was made even harder when Hassane Kamara was sent off for a second yellow card after 70 minutes.
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Watford could manage just a single shot on target at Selhurst Park, and mustered just 32% possession as Championship football for them next season was confirmed.
At Turf Moor, Steven Gerrard’s men went ahead after just seven minutes through former Southampton striker Danny Ings, before Argentine playmaker Emi Buendia scored the second just after the half-hour mark.
Seven minutes into the second half, Ollie Watkins made it three before an injury-time consolation for Maxwel Cornet.
Villa moved into 11th place with a game in hand on Brighton and Palace above them, while Burnley are just two points above the relegation zone.
Palace ended the game in ninth place on 44 points, six behind Wolves, who drew 2-2 at Stamford Bridge with Chelsea, who stay in third place.
Brentford swatted aside Southampton with goals from Pontus Jansson, Yoane Wissa and Kristoffer Ajer giving them a comfortable 3-0 win. Brentford ended the match 12th on 43 points, with Southampton in 15th.
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