The Saints came from 2-0 down to draw with Chelsea on Wednesday and are currently three points clear of the relegation zone.
Adkins, 47, took the club from League One to the Premier League with successive promotions and his win ratio of over 50% of games is tremendous. The former physio is reknowned in the game as a tactician and great man manager and one expert at least thinks the decision will end in tears.
Saints chairman Nicola Cortese said in a statement: "This decision has been made with the long-term ambitions of Southampton Football Club in mind.
"Whilst we acknowledge the contribution Nigel has made during the past two years, for the club to progress and achieve our long-term targets a change was needed.
"Mauricio is a well-respected coach of substantial quality who has gained a reputation as an astute tactician and excellent man manager.
"I have every confidence that he will inspire our talented squad of players to perform at the highest possible level."
The Argentine left Spanish side Espanyol in November and will lead training on Saturday for the first time.
Pochettino played for Espanyol and Paris Saint-Germain as a defender during his career, and won 20 caps for Argentina, fouling Michael Owen at the 2002 World Cup to give England a penalty which was converted by David Beckham.
Pochettino said: "This is the kind of opportunity that any coach would relish. Southampton is a club with great heritage, and an even more exciting future.
"There is a clear vision to take the club to a new era of sustained success in the Premier League, and beyond, which I'm delighted to be part of."
Pochettino took charge of Espanyol at the age of 36 in January 2009, and managed a best finish of eighth in La Liga in 2010-11.
He left the club by mutual consent at the end of November 2012, with an overall record of 49 wins from 146 league matches.
Former Southampton manager and vice-president of the League Managers' Association Lawrie McMenemy believes Adkins has been treated harshly.
He told BBC Radio 5 live: "Well I am shocked. I said right from the start that to finish fourth bottom in the first season in the Premier League is success.
"The ambition this year is to stay in the Premier League and they look set for that, not many teams will go to Chelsea and get a draw.
"With due respect to Pochettino, what does he know about our game? What does he know about the Premier League?
"What does he know about the dressing room, does he speak English?
"Everybody will be feeling sorry for Nigel Adkins. I don't think he'll have a problem getting another appointment."
A sentiment shared by leading football punter Joe Ross from footyinsider.co.uk.
'Punting on football is about managers. Good managers win games they shouldn't, grab points against the odds and basically over achieve. Adkins record in successive promotions suggests he is well above average in that regard.
'It took Adkins a few games to adjust to life in the Premier League but just two defeats in twelve games suggest he is getting to grips. No disrespect to Pochettino but Espanyol hardly set the world on fire and his win ration is below Adkins in a less competitive league.
'Instead of building on the last 12 games the players and back room staff will now be wondering what their long term future is. Southampton could end up nose diving down the table and the Board will only have themselves to blame. We will lay Southampton all day long. Everton look the bet of the weekend on Monday.'