The former Argentina international's stock has risen markedly since his controversial appointment at St Mary's in January 2013.
Having arrived in English football a relative unknown, former Espanyol manager Pochettino's possession-based, attacking game and focus on home-grown talent has impressed, as have his on-field results.
Southampton managed their best Barclays Premier League finish last season but, after months of speculation, will be now looking for a new head coach after Pochettino signed a deal until 2019 to succeed Tim Sherwood. "This is a club with tremendous history and prestige and I am honoured to have been given this opportunity to be its head coach," Pochettino told Spurs' official website. "There is an abundance of top-class talent at the club and I am looking forward to starting work with the squad.
"Tottenham Hotspur has a huge following across the world and I have great admiration for the passion the fans show for this team. We are determined to give the supporters the kind of attacking football and success that we are all looking to achieve."
Pochettino had a year remaining on his deal at St Mary's and has taken with him assistant manager Jesus Perez, first-team coach Miguel D'Agostino and goalkeeping coach Toni Jimenez.
It is unclear what those appointments mean for Spurs' existing backroom team, while there have been reports questioning the future of technical director Franco Baldini.
What is certain, though, is that Pochettino will be charged with securing Spurs a top-four finish by ambitious chairman Daniel Levy after a disappointing campaign, in which a flurry of summer signings failed to gel.
"In Mauricio I believe we have a head coach who, with his high energy, attacking football, will embrace the style of play we associate with our club," Levy said. "He has a proven ability to develop each player as an individual, whilst building great team spirit and a winning mentality.
"We have a talented squad that Mauricio is excited to be coaching next season."
Pochettino's Southampton future has been in doubt since the January departure of divisive executive chairman Nicola Cortese, having last summer claimed he would follow the Italian out of the club should he leave. The former defender did stay on at Saints after Cortese exited but only for a matter of months, with the club concluding negotiations with Spurs yesterday after accepting his resignation.
Malky Mackay, Steve McClaren, Murat Yakin and Michael Laudrup are amongst the early front-runners to replace Pochettino, while the departure will see speculation intensify over the future of Southampton's players. England duo Luke Shaw and Adam Lallana have attracted interest from Manchester United and Liverpool respectively, while Dejan Lovren, Calum Chambers and Jay Rodriguez have been linked with moves.
Last month executive director Les Reed said the club's intention was to keep their star players but Pochettino's exit will make that harder.
Chairman Ralph Krueger said in a statement published on the club's website yesterday: "The club has been on a constant path of growth since the arrival of Markus Liebherr in 2009. This growth took place before Mauricio came, it continued strongly under his leadership, and it will continue into the next season.
"The board's job is to find opportunity in this challenge and to continue to move the club forward.
"We have begun the search for a new high-calibre manager. We will be looking for a manager that shares our values, our principles and our philosophy."