The world No. 3 from Great Britain improved as a clay-court player but failed to add to his Grand Slam titles under Mauresmo.
Murray, who turns 29 in a week, said Monday that he and Mauresmo "mutually agreed" to end their partnership.
"I've learned a lot from Amelie over the last two years, both on and off the court,'' Murray said in the statement. "She's been a calming influence in the team and we will all miss having her around.
"I'll take some time to consider the next steps and how we progress from here, but I'd like to thank her for everything she has done. She's been an invaluable member of the team."
Murray became the first high-profile men's tennis player to hire a woman as a coach in June 2014.
Mauresmo, a former world No. 1 who gave birth to her first child in August and took six months off from coaching, said "dedicating enough time along with the travel has been a challenge for me.''
Mauresmo was in Spain as Murray lost the Madrid Open final to Novak Djokovic 6-2, 3-6, 6-3 on Sunday, but his new assistant coach, Jamie Delgado, took charge off the court.
"Working with Andy over the last two years has been a fantastic experience for me," said Mauresmo, who won the Australian Open and Wimbledon in 2006. "I've thoroughly enjoyed being part of the great team of people he has around him."
Murray is a two-time Grand Slam champion (U.S. Open in 2012, Wimbledon in 2013) and also won a gold medal at the London Olympics in 2012.
Murray will be playing the French Open, Wimbledon, Rio Olympics and U.S. Open in the next four months.