Dele Alli’s absence from Spurs’ match day squad was the big talking point as Tanguy Ndombele earned his first start since March, while Nathan Redmond missed out for the hosts.
Spurs raced into a first-minute lead after Harry Kane volleyed underneath Southampton goalkeeper Alex McCarthy, but a review from the Video Assistant Referee chalked off the strike.
The Saints also had the ball in the net on 16 minutes after Danny Ings got around Hugo Lloris to curl into an empty net, but it was ruled out after the forward was caught handling in the build-up.
Spurs still lived on the edge minutes later as Lloris punched James Ward-Prowse’s half-volley from close-range away while Moussa Djenepo struck the post later on following a first-time shot.
The hosts still drew first blood on 32 minutes after Ings brought down a ball over the top from the right for a clinical finish from the tightest of angles.
Spurs levelled deep in stoppage time when Heung Min-Son drifted onto the shoulder of the area before nestling the bottom corner following Kane’s first-time pass.
A substitution for Spurs at halftime saw Giovani Lo Celso enter in favour of Ndombele, as Jose Mourinho looked for control. Spurs surged ahead minutes later after Son beat the offside trap to slam home from close-range following Kane’s through ball.
Son rounded of his hat-trick on 64 minutes after going clear from a ball over the top to beat McCarthy with a composed finish.
The Korean wasn't done after allowing Kane’s cross-field pass on 73 minutes into his stride before finding his and the club’s fourth.
After assisting all four goals, Kane finally got on the scoreboard after reacting first to a rebound from the post to slot home.
Ings netted his second from the penalty spot in stoppage time after VAR penalised Matt Doherty for handling in the area- leaving Spurs to their first win at the end.