His resignation follows President Donald Trump's order to ban TikTok unless its parent company ByteDance sells its US operations to an American company within 90 days.
TikTok CEO Kevin Mayer has quit the company as tensions soar between Washington and Beijing over the Chinese-owned video platform.
Mayer's resignation on Thursday comes days after TikTok filed a lawsuit challenging a crackdown by the US government over claims the wildly popular social media app can be used to spy on Americans.
TikTok has been at the centre of a diplomatic storm between the US and China, and President Donald Trump signed an executive order on August 6 giving Americans 45 days to stop doing business with TikTok's Chinese parent company ByteDance – effectively setting a deadline for a sale of the app to a US company.
TikTok, which has been downloaded 175 million times in the US and more than a billion times around the world, argued in the suit that Trump's order was a misuse of the International Emergency Economic Powers Act because the platform –– on which users share often playful short-form videos –– is not "an unusual and extraordinary threat."
'Political environment has sharply changed'
Former Disney executive Mayer, who has only been in the post since May, said in a letter to staff that "in recent weeks, as the political environment has sharply changed, I have done significant reflection on what the corporate structural changes will require, and what it means for the global role I signed up for".
"Against this backdrop, and as we expect to reach a resolution very soon, it is with a heavy heart that I wanted to let you all know that I have decided to leave the company," he wrote.
"I understand that the role that I signed up for –– including running TikTok globally –– will look very different as a result of the US administration's action to push for a sell-off of the US business."
TikTok said in a statement: "We appreciate that the political dynamics of the last few months have significantly changed what the scope of Kevin's role would be going forward, and fully respect his decision.
We thank him for his time at the company and wish him well."