The Portuguese oversaw a slew of unwanted records at the 20-time English champion including its lowest finish in the Premier League era last season.
Ruben Amorim has been sacked as Manchester United manager 14 months after arriving at Old Trafford, the English Premier League club announced on Monday.
The decision comes a day after he made provocative comments about his position following a 1-1 draw with Leeds.
"With Manchester United sitting sixth in the Premier League, the club's leadership has reluctantly made the decision that it is the right time to make a change," United said in a statement.
"This will give the team the best opportunity of the highest possible Premier League finish."
United said youth coach Darren Fletcher would take charge of its match against Burnley on Wednesday.
The Portuguese oversaw a slew of unwanted records at the 20-time English champion including its lowest finish in the Premier League era last season.
The United job has proved one of the most difficult in world football since club legend Alex Ferguson retired in 2013, with Amorim the sixth permanent manager to be discarded in that time.
Amorim apologised to fans at the end of last season for what he described as a "disastrous" campaign when United finished 15th in the standings, recorded its highest number of losses in a Premier League season and lowest points total.
Last week there were reports that figures at the club had questioned his tactics and on Sunday he sought to clarify his position.
"I came here to be the manager of Manchester United, not to be the coach of Manchester United," he said. "And that is clear."
"I'm not going to quit. I will do my job until another guy is coming here to replace me."