Gottfried was in his sixth season as assistant general manager for player relations, a position he took in 2006. He was previously the club's senior director of baseball operations and earlier the director of Minor League administration.
He joined the Astros in 1998 as a baseball operations assistant.
"I really enjoyed my time there and am proud of the contributions I've made over the last 14 years," Gottfried said. They've decided to go in another direction, and I'm looking forward to my next opportunity."
Gottfried's departure is the latest in a series of front office moves by the Astros that included assistant general manager/director of scouting Bobby Heck and director of professional scouting Ricky Bennett not having their contracts renewed.
Prior to joining the Astros, Gottfried spent five years with the Oakland A's Class A affiliate in Modesto, Calif., serving as GM for two years. He also worked for the Arizona Fall League.