Assistant boss Mark Venus has been placed in temporary charge of the first team, although ex-Stoke manager Tony Pulis has emerged as an early frontrunner for the role on a permanent basis.
Former Boro centre-back Mowbray was named manager in 2010 but the Teessiders have won just two of their opening 12 Championship matches and lie 16th in the table.
Mowbray failed to take the club back into the Premier League during his time at the Riverside Stadium, as they finished 12th, seventh and then 16th last season under his guidance.
His final game in charge was Saturday's 3-2 defeat to Barnsley.
"Middlesbrough have announced that manager Tony Mowbray has left the club with immediate effect," read a statement on the club's official website.
"Assistant manager Mark Venus will take charge of the team until further notice.
"The club would like to place on record their sincere thanks to Tony Mowbray for all of his substantial efforts, dedication and integrity.
"He leaves with the very best wishes of all at the club."
Middlesbrough host Doncaster on Friday night and you can see how they get on without Mowbray - the match is live on Sky Sports 1 HD from 7:30pm.