Pochettino moves to White Hart Lane to replace Tim Sherwood, who saw a break clause in his contract activated after leading the club to sixth in the Premier League.
The former Argentina defender has enjoyed a hugely fruitful 16 months on the south coast, leading Southampton to a record Premier League points tally and eighth place in 2013-14.
Highlighting the success at St Mary's Stadium has been the breakthrough of four Southampton players into the England squad - Adam Lallana, Rickie Lambert, Jay Rodriguez and Luke Shaw.
Only Rodriguez from that quartet will not travel to the FIFA World Cup in Brazil, due to a season-ending knee injury, and Pochettino's faith in homegrown talent has impressed.
His focus will now switch to Spurs' perennial quest to finish in the Premier League's top four and secure UEFA Champions League qualification.
Southampton confirmed that Pochettino had resigned his post at St Mary's, and he will be joined in his new role by many of the staff he appointed on the south coast.
He told Tottenham's official website: "This is a club with tremendous history and prestige and I am honoured to have been given this opportunity to be its head coach.
"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."
Club chairman Daniel Levy added: "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.
"He has a proven ability to develop each player as an individual, whilst building great team spirit and a winning mentality."
Southampton, meanwhile, have turned their focus to finding Pochettino's replacement, with chairman Ralph Krueger highlighting the need to bring in a similarly high-performing coach.
Krueger said: "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.
"The club has been on a constant path of growth since the arrival of (former owner) 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."
