Flake went on to blast Trump and Republicans in a Senate speech, accusing his party of abandoning "core principles" in favor of "anger and resentment."

Flake faced a tough primary battle, as well as ongoing fights with Trump and former White House chief strategist Stephen Bannon, who had backed his primary challenger.

The Arizona Republic first reported Flake's decision Tuesday afternoon, minutes before the first-term senator took to the Senate floor to say he felt out of step with his party.

"It is clear at this moment that a traditional conservative who believes in limited government and free markets, who is devoted to free trade, and who is pro-immigration, has a narrower and narrower path to nomination in the Republican party — the party that for so long has defined itself by belief in those things," Flake said during the speech.

"It is also clear to me for the moment we have given in or given up on those core principles in favor of the more viscerally satisfying anger and resentment," he said.

In the speech, he repeatedly slammed Trump, criticizing the example he's setting for America's children, accusing him of railroading "civility and stability" and accusing Republicans of mistaking "reckless, outrageous and undignified behavior" for authenticity.

"If I have been critical, it not because I relish criticizing the behavior of the president of the United States. If I have been critical, it is because I believe that it is my obligation to do so, as a matter of duty and conscience," he said.

"The notion that one should stay silent as the norms and values that keep America strong are undermined and as the alliances and agreements that ensure the stability of the entire world are routinely threatened by the level of thought that goes into 140 characters — the notion that one should say and do nothing in the face of such mercurial behavior is ahistoric and, I believe, profoundly misguided."

Flake's comments were magnified by the harsh criticism of Trump levied by Corker just hours before, who said Trump is "debasing" the country and that he regrets supporting his candidacy. Taken together, the condemnation from two Republican senators embodies the deep fissures within the party and the unease among the party establishment as Trump remakes the party in his image.

While the Arizona senator has a sterling reputation with Republicans on Capitol Hill and a conservative voting record, he's frustrated those on his party's right flank with his repeated attacks on Trump.

Flake never endorsed Trump during the presidential race, and later went on a book tour accusing Trump of leading his party and country astray.

Flake's antagonistic approach to Trump prompted the president and allies to begin plotting support for a primary challenge to take him down from the right. Trump's White House met with potential candidates over the summer, but ultimately, only former state Sen. Kelli Ward decided to jump in.

Earlier this month, Bannon endorsed Ward, who had led a handful of public polls. That endorsement and Trump's favorable tweets about Ward during the summer were a signal to many Arizona Republicans dissatisfied with Flake that they should rally behind her challenge.

But Flake's decision could upend the GOP field, since some potential candidates who had been reluctant to challenge a sitting senator now find themselves faced with a far more favorable field. Flake's exit could also leave the Republican-held seat more vulnerable than before, setting up a mammoth 2018 clash between the parties. Even with Bannon's support, Ward had not been considered the strongest possible GOP candidate for the general election. Democrats believe that she's too controversial to win.

David Bossie, Trump's former deputy campaign manager, wrote an op-ed on Monday for Fox News where he called Gosar a "dynamic conservative reformer" if he were to run for the seat.

The decision also complicates the calculus for the general election, where Democratic Rep. Kyrsten Sinema is expected to cruise to her party's nomination.

— Lisa Hagen and Scott Wong contributed