The Stags lie 18th in League Two with one win in 11 games, and lost 4-0 at Portsmouth on Saturday.
"I have been with the club for over 14 years and having discussed it with my management team we have decided it is time for a change," the ex-player said.
Under-21s head coach Mike Whitlow and youth team manager John Dempster will take temporary charge with Mansfield set to host Crawley on Saturday.
First-team coaches Karl Hawley and Richard Cooper have also left Field Mill.
Murray had pledged his future to the club 11 days ago after reports he would quit.
Chairman John Radford said: "I've worked with Adam for a long time and respect him immensely. The decision by Adam to part ways was made with a very heavy heart.
"Adam will always be in Mansfield Town's hall of fame. He has served the club magnificently as both a player and for almost two years, a manager, and I sincerely wish him well for the future."
Murray was placed in caretaker charge - with the Stags sitting 19th in League Two - following the departure of Paul Cox in November 2014 and his appointment was made permanent a month later.
He helped the Stags avoid relegation and last season he led them to a 12th-placed finish, 11 points adrift of the play-off places.
Adam Murray has resigned as Mansfield Town manager after two years in charge.