Flake, perhaps Trump's most vocal Republican critic in Congress, delivered his plea in a tweet Tuesday evening, echoing his words from a Washington Post interview earlier that day.
"To fire Mueller without cause, I don't know if there is any other remedy left to the legislative branch" besides impeaching the president, Flake told the Post.
Trump raised concerns about Mueller's job security in a series of aggressive tweets sent over the weekend. For the first time since Mueller was appointed in May 2017, Trump criticized the former FBI director by name on Twitter.
A steady trickle of congressional Republicans chimed in after the weekend tweet storm to reaffirm their support for the special counsel's unfettered ability to investigate potential links between the Trump campaign and Russia.
House Speaker Paul Ryan, R-Wisc., said Tuesday that "the special counsel should be free to follow through his investigation to conclusion."
He was later joined by Senate majority leader Mitch McConnell, R-Ky., who said, "I agree with the president's lawyers that Bob Mueller should be allowed to finish the job."
Flake's comments also followed reports from the Post and the New York Times that Trump's legal team could soon experience a shakeup for matters related to its handling of the Mueller investigation.
The Times reported Tuesday that Trump has openly considered firing lawyer Ty Cobb, who is said to be a proponent of a hands-off approach to the Mueller probe. And lead White House lawyer John Dowd has reportedly considered resigning over Trump's uncontrollable personality.
Trump's lawyers and other White House officials pushed back on the report, maintaining that the legal team remains intact.