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 Sunday.
That left United sixth in the table, 19 points behind the Premier League leaders after 17 games.
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."
Manchester United has announced that Jose Mourinho has left the Club.
We would like to thank him for his work during his time at Manchester United and wish him success in the future. #MUFC
— Manchester United (@ManUtd) December 18, 2018
Mourinho was hired at the end of the 2015-16 season to replace Louis van Gaal and he won the Europa League and EFL Cup in his first campaign at Old Trafford.
They finished sixth in the Premier League that season and were runners-up last year behind a Manchester City side that finished 19 points ahead of them.
However, this year United have been left cut adrift of City and Liverpool in the Premier League and they have won just one of their last five games in all competitions.
Mourinho has also clashed with players in his own team throughout his tenure, including the likes of Luke Shaw, Anthony Martial and Paul Pogba.
The latter, United's record signing, was left on the bench on Sunday as United suffered defeat to Liverpool, who registered 36 shots on goal across the 90 minutes.
Mourinho stated after that loss that the best United can hope for this season is a top-four finish and subsequent Champions League qualification.
However, United are already 11 points adrift of fourth-placed Chelsea and eight behind Arsenal in fifth.
United will now begin searching for their fourth permanent manager since Alex Ferguson retired from the post after winning the club's 20th domestic league title in 2012-13.
It has been reported that United's caretaker manager for the remainder of the 2018-19 season will be an external candidate and that the club hope to have someone in place in the coming days ahead of Saturday's trip to Cardiff City.
Michael Carrick, who joined Mourinho's coaching staff on a full-time basis after retiring from playing at the end of last season, is expected to take training in the meantime.
Photo Getty Images. Caption: Manager Jose Mourinho