Ryan Sessegnon scored his first Premier League goal for Tottenham
Spurs fell behind in the 12th minute to James Ward-Prowse's volley - the midfielder driving the ball into the ground and watching the bounce beat Hugo Lloris - but the response from Antonio Conte's side was swift and ruthless.
Ryan Sessegnon headed in his first Premier League goal for the club from an inviting Dejan Kulusevski cross to draw the hosts level and by the half-hour mark they were in front.
Eric Dier had not scored in three years but met a whipped Son Heung-min delivery with a low, flicked header into the far corner.
Tottenham carried that confidence into the second half and Mohammed Salisu turned Emerson Royal's cross into his own net, before the impressive Kulusevski grabbed a well-taken fourth to cap a stylish and dominant display.
"We won three important points but the most important thing was the way we got three points - with really good football, with the ball, without the ball, with important pressure," said Conte. "The way we decided to win the ball after we lost it was another important aspect.
"We are working to implement football knowledge over the last season. We have seen this team has seven months of work on its back."
Eric Dier scored his first Tottenham goal since May 2019
A full pre-season under Conte, six new signings and permission to be "dreamers" from their Italian boss means Spurs fans will be expecting big things from their side.
"Why not winning the Champions League and the Premier League?" Conte joked beforehand, though it took Ward-Prowse's strike, following smart play from Moussa Djenepo, to spark his side into life on the opening day.
With Richarlison suspended and other new recruits still building up to full fitness, there was a familiar look to the Spurs XI, albeit with two unfamiliar names on the scoresheet.
Sessegnon and Dier have been two of the biggest beneficiaries of the Conte era, and both took their headers well to put Spurs in front - the more predictable sources of Son and Kulusevski producing moments of quality to tee up both defenders.
"He was always in our offensive position and it was good," Conte said of Sessegnon, adding that the 22-year-old can learn from experienced new arrival Ivan Perisic.
"I'm happy for him because he has great potential, but has to show this potential."
This was the first time Tottenham have played a home Premier League game at 3pm on Saturday in 973 days, since beating Burnley 5-0 in December 2019, and the first time they have begun a season in this kick-off slot for more than 20 years.
Rarely in those two decades has there been as much optimism in north London and that is unlikely to have been dampened by what for the most part was a confident and entertaining performance.
Sessegnon also had an effort ruled out for offside immediately after the break and opposite wing-back Royal's low ball forced Salisu into an own goal, before the Brazilian teed up Kulusevski to find the bottom corner two minutes later.
The focus at Southampton has been on youth this summer after signing six players with just two over the age of 20, but it was Saints' Mr Reliable - and last season's top scorer Ward-Prowse - who got the visitors off to a superb start.
That hope was short-lived for Ralph Hasenhuttl's side who, as well as having the worst opening-day record of all current Premier League teams, finished last season with four successive defeats and did little to rid themselves of that hangover at the Tottenham Hotspur Stadium.
"It felt a little bit like the opponent switched into the next gear and we cannot follow," said the Saints boss. "This was frustrating to see how big the gap is between the two teams.
"After the first goal we had the feeling they were absolutely in the game and they smashed us with their crosses and we couldn't defend."
-- Courtesy of BBC Sport