Heung-min Son started up front in Harry Kane's absence but it was Christian Eriksen and Dele Alli who assumed goalscoring responsibilities at White Hart Lane to put Spurs in front at the break.
The Saints hit back through James Ward-Prowse's close-range finish but Mauricio Pochettino's side dug in to extend their stellar home record and simultaneously tighten their grip on second place.
Son ran the line diligently and was presented with an early chance following Kyle Walker's measured pass but the South Korean fired an effort straight at Fraser Forster.
Southampton forced several early errors from their hosts and only a marginal offside call denied Manolo Gabbiadini an opportunity to break the deadlock.
But thee visitors' hard work was undone when Christian Eriksen was gifted too much space outside of the area, allowing the Dane to pick his spot and rifle an effort into the bottom corner of the net.
Yet the opening goal did not knock Southampton out of their stride and Oriol Romeu's vicious volley served as a reminder that the resolve of the South Coast club had not been broken.
Forster produced a superb scooped save to deny Toby Alderweireld while Gabbiadini gave the away fans a moment to celebrate before they realised their new hero's shot had flown into the side netting rather than nestled in the top corner.
Gabbiadini's afternoon was over moments later and the striker cut a forlorn figure as he trotted down the tunnel nursing a groin problem.
Spurs were not in a sentimental mood and doubled their lead just after the half hour mark when Alli was fouled by Steve Davis before picking himself up and firing past Forster from 12 yards.
Dusan Tadic was sent tumbling by Ben Davies on the stroke of half time but referee Andre Marriner waved Southampton's hopeful calls for a penalty away.
Claude Puel sent his players out early, seemingly intent on witnessing a reaction, and it arrived in the 52nd minute when James Ward-Prowse collected Ryan Bertrand's cross before beating Hugo Lloris from close range.
The north Londoners were forced to endured a wave of pressure but stood firm during the closing stages - with Alli ushered up front after Son's withdrawal - to record a 10th consecutive top-fight victory in N17.