United are currently sixth in the Premier League, some 11 points off the top four and 19 behind leaders Liverpool after a hugely disappointing start to the season.
Despite steering the Reds to the last 16 of the Champions League, the Red Devils had won only one of their last six Premier League matches and on Sunday lost 3-1 to Jurgen Klopp's league leaders.
With that defeat, United surpassed their goals against total from last season after just 17 league matches of the current campaign.
"The club would like to thank Jose for his work during his time at Manchester United and to wish him success in the future," read a three-paragraph statement on Manchester United's official website.
"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."
Mourinho's departure comes three years and one day after he left Chelsea under a cloud in 2015, when the Blues were 16th in the Premier League.
Fans had been worried about an increasingly toxic atmosphere at Old Trafford, amid Mourinho's regular public criticism of his players and reports that some were even unhappy with medical treatment at the club.
His fractured relationship with Paul Pogba has dominated headlines all season, while the Portuguese's regular dropping of other big-name stars and his own exensive signings has been a regular source of ire.
Michael Carrick has been placed in charge as interim manager, but United are expected to confirm an external appointment until the end of the season this week.
