The decision comes with the club sat sixth in the table after just one win in their last five games, including a 1-1 draw against bottom-placed Wolves.
His tenure also included reaching the Europa League final in the 2024/25 campaign and recording a 15th-placed finish in the Premier League.
"Ruben Amorim has departed his role as Head Coach of Manchester United," the club said in a statement.
"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. This will give the team the best opportunity of the highest possible Premier League finish.
"The club would like to thank Ruben for his contribution to the club and wishes him well for the future.
"Darren Fletcher will take charge of the team against Burnley on Wednesday."
Amorim recently claimed that he was the manager of his team rather than a coach and that he would be gone once his contract expired, unless the board decided to replace him
"I'm not going to quit. I will do my job until another guy is coming here to replace me," he said.
"I'm going to be the manager of this team, not just the coach.
"That is going to finish in 18 months and everyone is going to move on. That was the deal. That is my job, not to be a coach.
"I just want to say that I came here to be the manager of Manchester United, not to be the coach.
"Every department - the scouting department, the sporting director - needs to do their job. I will do mine for 18 months, and then we move on."
He was also said to be left frustrated by the club's transfer plans.
Darren Fletcher is due to take interim charge of the club, starting with a clash against Burnley on Wednesday, January 7th.