Flyers president Paul Holmgren cited philosophical differences as the main reason for the decision.
"We thank Ron for his many significant contributions, but it has become clear that we no longer share the same philosophical approach concerning the direction of the team," Holmgren said in a statement. "... We feel it's in the organization's best interests to make a change, effective immediately. I have already begun a process to identify and select our next general manager."
The Flyers sit fourth-last in the Eastern Conference and have allowed the third-most goals against in the league.
Hextall, a former netminder, was unable to address the club's goaltending woes. Brian Elliott (14 games), Calvin Pickard (11 games), Anthony Stolarz, Alex Lyon, and Michal Neuvirth (one game apiece) have combined for an .887 save percentage and a 3.35 goals-against average this season.
Hextall remained loyal to head coach Dave Hakstol, despite "Fire Hakstol!" chants last season and the team's poor start to the 2018-19 campaign.
Hextall had been Flyers GM since May 7, 2014. Philadelphia made the playoffs twice during his tenure but the team was ousted in the first round each time.