The Pirates also announced the hiring of Travis Williams as the club's new team president. He will replace Frank Coonelly, who was fired last week.
"I greatly appreciate Neal's dedication to the Pirates organization and our city over the past 12 seasons," Pirates owner Bob Nutting said in a statement Monday. "His time with the Pirates should always be remembered for ending a long stretch of futility and bringing postseason baseball back to Pittsburgh.
"This past season was by far the most frustrating and challenging season that I have experienced as owner. It became clear to me as the season progressed that significant change was necessary in order to refresh our entire operations."
Huntington, 50, served as general manager since replacing Dave Littlefield after the 2007 season. Kevin Graves, who has been the Pirates' assistant general manager, will take over the role on an interim basis until a replacement is found.
The Pirates also fired manager Clint Hurdle, pitching coach Ray Searage and bench coach Tom Prince following the regular season. Pittsburgh finished last in the NL Central this season, posting a 69-93 record and missing the playoffs for the fourth straight year.
Williams, who spent 11 seasons as the chief operating officer of the NHL's Pittsburgh Penguins, will officially begin as the Pirates' president Friday.