Gareth Bale had Spurs ahead against his former club after 17 minutes when he headed home a Jermain Defoe cross in assured fashion.
Spurs dominated possession throughout the first half and went two goals ahead before the break when Clint Dempsey was on hand to tap home after Defoe's shot came agonisingly close to crossing the line.
Saints were booed off by their own fans after a torrid 45 minutes but Nigel Adkins's side responded well in the second half.
Kyle Walker flashed an effort wide on the hour before mounting Southampton pressure led to a goal five minutes later.
Chaos reigned in the Spurs defence as Jay Rodriguez made no mistake to send the ball high into the net for his first Saints goal.