Lloris began the game strongly when he tipped Pierre-Emile Højbjerg's effort wide of the goal, showing great reflexes and sharpness.
Southampton enjoyed a spell of pressure early in the second half, but they did not really threaten an equaliser and slipped to a third defeat of the season.
The Saints may have counted themselves lucky with the sending off, as moments before the ball seemed nearly definitely out of play.
With the momentum changed, the France captain inexplicably handed Southampton a way back into the game when he tried performing a Cruyff turn in his own six-yard box only to be tackled by Danny Ings, whose toe-in rolled over the line.
It has been an up and down start to the season for Spurs, who lost to Leicester in the league and were eliminated from the Carabao Cup by Colchester United in the two games preceding the match with the Saints.
In the end, and perhaps unsurprisingly, Spurs saw it out with relative ease to produce a vital three points.
"We said at half time, 'this is the moment to prove that we are a team, ' and it was important to get three points today, and more important not the way we played on the ball, but off the ball".
When Ndombele signed from Lyon, Tottenham fans knew they were getting a talented young player with huge potential, but some were skeptical whether he could fill the boots of Mousa Dembele straight away.
Spurs have been besieged by problems after a summer of unrest in the dressing room, where a host of key players were uncertain of their future.
"But we showed character and we showed personality, I am just happy my mistake did not cost us any points".
"You don't need to blame Hugo, blame me because I demand him to play in that way". A few situations that could be a tough impact in a negative way today we showed an wonderful spirit.
"I think this [Southampton] was a game that, maybe in the period that we think that we are then we could have lost easily, because after 30 minutes if you get a red card and then you concede like this, it had all the ingredients to lose the game and I think we were wonderful", the Belgian defender said.
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