McGwire informed the team he was leaving his position to spend more time with his family.
"He wants to watch his two boys play high school baseball," manager Andy Green said in a text to the Associated Press. "We talked about it a lot before the season ended."
McGwire lives in Irvine, California, in southern Orange County and had spent three seasons on the Padres' staff.
McGwire's decision comes after nine seasons in a big-league coaching role — three as hitting coach with the Cardinals, three as hitting coach with the Los Angeles Dodgers and the last three in San Diego.
The Padres will now look to fill three coaching positions, including bench coach, infield coach, and hitting coach as the team prepares to enter the offseason. Matt Stairs and Josh Johnson were not retained as hitting coach and infielders coach, respectively.
San Diego finished the 2018 regular season at 66-96 and 5th place in the National League West. They were ranked 28th in runs scored (617) and batting average (.235)