The former Disney executive has stepped down from the job just six months after joining the video sharing platform.
A TikTok spokesperson told The Verge: "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."
Mayer reportedly announced his exit in an email obtained by the Financial Times, in which he claimed the current "political environment" made him decide it was best for him to resign.
In the letter, he stated: "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."
According to the newspaper, TikTok's general manager Vanessa Pappas will replace him in the interim.
Mayer's exit comes as TikTok revealed they are suing Trump's Administration.
The video platform alleged that the world leader's stance against them is unjust and has nothing to do with Trump's allegations that the app's Chinese-based parent company, ByteDance, poses a national security threat.
ByteDance said in a statement: "The Executive Order issued by the Administration . . . has the potential to strip the rights of that community without any evidence to justify such an extreme action, and without any due process.
"We strongly disagree with the Administration's position that TikTok is a national security threat and we have articulated these objections previously."
In their lawsuit, the firm has claimed Trump's Administration has ignored TikTok's attempt to address the issues "in good faith" with the Committee on Foreign Investment in the US.
They continued: "Now is the time for us to act. We do not take suing the government lightly, however we feel we have no choice but to take action to protect our rights, and the rights of our community and employees. In our complaint we make clear that we believe the Administration ignored our extensive efforts to address its concerns, which we conducted fully and in good faith even as we disagreed."
ByteDance believes the government's issues with the app "is not rooted in bona fide national security concerns".
Trump has given the company an extended deadline, until November 12, to sell TikTok to an American firm, or face having the app banned from the country.
The likes of Microsoft, Oracle, and Twitter have expressed an interest in purchasing the app.