Saints' fate had felt inevitable for months, and a first-half brace from Brennan Johnson on Sunday offered Ange Postecoglou's struggling Spurs some relief while setting the visitors on course for an immediate return to the Championship.
Meanwhile, at the other end of the table, Liverpool suffered their first away defeat of the season in the league, beaten 3-2 by Fulham at Craven Cottage as their seemingly inevitable charge towards the title hit an unexpected roadblock.
At the Tottenham Hotspur Stadium, Mateus Fernandes grabbed a late consolation for Southampton before Mathys Tel struck a stoppage-time penalty for Spurs to codemn the Saints to the drop with seven fixtures left.
That gives Southampton an unwelcome Premier League record. For while Derby and Huddersfield, in 2008 and 2019 respectively, had their fate sealed even earlier in March, both had only six matches to go compared to Southampton's seven.
The three points for Tottenham lifts some of the gloom around Postecoglou's side ahead of Thursday's Europa League quarter-final first leg at home to Eintracht Frankfurt, a fixture that could determine the Australian's fate at Spurs.
Liverpool failed to take advantage of Arsenal dropping points a day earlier, but still remain on course to win a record-equalling 20th English league title as they're 11 points clear of second-placed Arsenal, who drew 1-1 with Everton on Saturday.
Defeat at Craven Cottage was only Liverpool's second in the league all season and came despite Alexis Mac Allister opening the scoring in the 14th minute.
Goals from Ryan Sessegnon, Alex Iwobi and Rodrigo Muniz saw Fulham lead 3-1 at halftime, before Luis Diaz got Liverpool's second after the break.
Arne Slot's team now need 11 points from the remaining seven games to be crowned champions.
Brentford are still searching for their first home league win of the year after a goalless draw with top-four chasing Chelsea, whose last away league victory came four months ago.
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