United revealed the news in a short media release less than 48 hours after a 3-1 Premier League loss to Liverpool at Anfield on Monday morning (AEDT).
A United statement read: "Manchester United announces that manager Jose Mourinho has left the club with immediate effect.
"The club would like to thank Jose for his work during his time at Manchester United and to wish him success in the future.
"A new caretaker manager will be appointed until the end of the current season while the club conducts a thorough recruitment process for a new full-time manager."
Assistant coach Michael Carrick will take charge of the team on an interim basis.
United made its move with the team in sixth place in the league, 19 points behind first-place Liverpool and 11 points off fourth-place Chelsea in the race for UEFA Champions League qualification.
It is United's worst 17-game start to a league campaign since the 1990-91 season, and the team currently has a goal difference of zero.
Mourinho started his two-year tenure at United by winning two titles in his first season - the English League Cup and the UEFA Europa League - but failed to win a trophy in his second season and was criticised for the team's pragmatic playing style and his treatment of some players.
His relationship with Paul Pogba, the club's record signing, appeared broken after leaving the France midfielder out of the team for its last three league games.
Mourinho had also been unhappy that United's board failed to back his wish to sign a central defender in the off-season. United has already conceded more goals in the league than it did in all of last season.
Mourinho's final match in charge was the 3-1 loss at Anfield, after which he said his players were brittle and couldn't cope with the intensity and physicality of Liverpool - historically United's biggest rival.
Mourinho lasted the same length of time at United as he did in his previous job at Chelsea, when he was also fired just before Christmas in his third season.
He signed a new contract in January until June 2020 and will reportedly receive compensation of 24 million pounds ($42.18 million).
In his six major coaching stints - at Porto, Chelsea, Inter Milan, Real Madrid, Chelsea again and United - Mourinho has only lasted more than three years once. That was in his first spell at Chelsea.
United reached the last 16 in the Champions League, where it will play Paris Saint-Germain over two legs in February and March.
