Owner Jerry Richardson said in a statement he made the decision after a long evaluation of the team's football operations.
"I want to thank Dave for the role he played in our success over the past four seasons," Richardson said. "While the timing of this decision is not ideal, a change is needed."
Armstrong: Panthers firing of GM is a head-scratcher
Gettleman had been Carolina's general manager for four seasons, when the Panthers went 43-26-1. But Carolina was 6-10 last season a year after reaching Super Bowl 50, where it lost to Denver. The Panthers had won the NFC South his first three years at the helm.
Gettleman made some business decisions that were unpopular with fans after taking over for Marty Hurney in 2013. Among them: cutting star wideout Steve Smith before the 2014 season and running back DeAngelo Williams in 2015, then allowing cornerback Josh Norman to become a free agent in 2016 after rescinding the franchise tag. Norman signed with Washington.
Williams, now a free agent after two seasons with Pittsburgh, tweeted he would consider returning to the Panthers "due to the firing of that snake Dave Gettleman!"
Smith, arguably the franchise's most popular player, never took the move well.
After learning of the news of Gettleman's firing, Smith tweeted "It's Okay! Dave I know how you feel..."
Linebacker Thomas Davis is in the final year of his contract and was hoping for an extension before the start of training camp. Pro Bowl tight end Greg Olsen is also hopeful of an extension, although he has two years left on his current deal.
The Panthers report to Wofford College in Spartanburg, South Carolina, on July 25 and have their first practice the following day.
Richardson did not say who would be responsible for personnel in the interim. The Panthers are also without a team president after Danny Morrison resigned in February.
Former assistant general manager Brandon Beane left in May to become Buffalo's general manager, reuniting him with Sean McDermott, who was Carolina's defensive coordinator for six seasons (2011-16).
Gettleman is the second NFL GM fired in less than a month. Kansas City fired John Dorsey on June 23.
The Associated Press contributed to this report.