The AMC horror drama, based on a comic series, stars Andrew Lincoln, Norman Reedus, Danai Gurira and Laurie Holden as survivors in a zombie apocalypse.
Mazzara explained: "My time as showrunner on The Walking Dead has been an amazing experience, but after I finish season three, it's time to move on.
"I have told the stories I wanted to tell and connected with our fans on a level that I never imagined. It doesn't get much better than that.
"Thank you to everyone who has been a part of this journey."
In a statement on Mazzara's exit, AMC said: "Both parties acknowledge that there is a difference of opinion about where the show should go moving forward, and conclude that it is best to part ways.
"This decision is amicable and Glen will remain on for post-production [until the end of season three] as showrunner and executive producer."
Mazzara had served as showrunner following the abrupt departure of creator Frank Darabont early into the second season.
The Walking Dead's third season will return in 2013.
Watch a promo for The Walking Dead's 2013 return below: