The former Tottenham and Chelsea boss replaces the outgoing Michael Carrick, who was sacked on Thursday following a meeting between United chiefs in Monaco.
In turn, Pochettino leaves the United States national team to make his Premier League return, despite signing a new contract to 2030 in August.
United have reportedly paid a $10 million (£7.5m) fee to release the ex-Argentina defender from his deal with US Soccer, with additional payments made for his staff members.
Pochettino is set to coach his remaining games with the USA in the current international break before officially starting at United on Wednesday, November 18th.
He arrives at Old Trafford with United 18th and in the Premier League relegation zone with one win from 10 games, their worst domestic start in 40 years.
His first game at the helm is a trip to Liverpool next Sunday following the international break.
Pochettino, whose coaching career started with Espanyol, arrived in the Premier League in January 2013 to manage Southampton.
He was appointed by Tottenham in 2014 and turned the club into a regular Champions League outfit, leading them to the final in 2019 before departing six months later.
Pochettino was hired by Paris Saint-Germain in January 2021 and won three trophies, including the 2021/22 Ligue 1 title in one and a half years.
He spent the 2023/24 campaign at Chelsea before leaving at the end of the season and taking up the United States job later that year.
Pochettino guided the USA to the last 16 stage of the World Cup in the summer.
