In his resignation letter, provided to ABC News, Gottlieb says he will stay on in his job for another month but he does not cite a reason for his leaving.
"I’m fortunate for the opportunity that the President of the United States afforded me to lead this outstanding team, at this time, in this period of wonderful scientific advances. I’m deeply grateful for your support and the support of the President and his team in advancing many critical public health goals," he wrote.
Gottlieb has presided over a number of FDA initiatives including faster approvals for generic drugs and cracking down on unproven procedures like thermography. He also worked to ensure food inspections and other essential services continued during the government shutdown.
News of his resignation comes a day after he announced new measures aimed at stores including Walgreens, 7-Eleven and Exxon. In a public rebuke on Monday, Gottlieb highlighted hundreds of incidents where some of the country’s top convenience store chains were found to have sold tobacco products to minors.
The agency has issued warning letters to retailers and e-cigarette manufacturers, requiring them to detail plans for correcting violations.
He said in his letter that he expects FDA to continue those initiatives.
President Donald Trump thanked Gottlieb in a tweet, saying he did an "absolutely terrific job" at FDA.
ABC News' Quinn Owen contributed to this story.