The onslaught from Jeff Flake and Bob Corker marked a sharp increase in tensions in what has been a fraught relationship between the president and congressional Republicans as Trump tries to enact his policy agenda.
Senator Flake, of Arizona, assailed Mr Trump in a bombshell 17-minute speech on the Senate floor, hours after the president made what was meant to be a bridge-building trip to the Capitol to drum up support for his tax reform plans.
Senator Flake, who has served in the Senate since 2013 and has been an outspoken critic of Trump-era politics, displayed visible emotion as his voice repeatedly broke as he announced he would not run for office again next year.
"The personal attacks, the threats against principles, freedoms and institutions, the flagrant disregard for truth and decency - the provocation for the most petty reasons... none of these appalling features of our current politics should ever be regarded as normal," the 54-year-old said.
"We must stop pretending that the degradation of politics and the conduct of some in our executive branch are normal. They are not normal.
"Reckless, outrageous and undignified behavior is excused as telling it like it is when it's actually just reckless, outrageous and undignified."
Senator Flake blasted Trump for his unfettered tweeting and attacked his Republican colleagues for keeping quiet as the president flouts one custom after another.
"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," he said.
"Politics can make us silent when we should speak and silence can equal complicity," added the senator, who has assailed Trump-style politics in a book entitled "Conscience of a Conservative."
"I have children and grandchildren to answer to.... I will not be complicit or silent.... I am announcing today that my service in the Senate will conclude at the end of my term in early January 2019."
'Political price'
Senator Flake's extraordinary speech came as a Senate colleague, Bob Corker of Tennessee, stepped up a war of words with Trump, calling him an "utterly untruthful" leader who "debases" the nation.
Like Senator Flake, Senator Corker is not seeking re-election next year.
Immediately after Senator Flake's speech, his senior colleague from Arizona, Senator John McCain, praised him for his "honour", "brilliance" and "patriotism."
"I have seen Jeff Flake stand up for what he believes in, knowing full well that there would be a political price to pay," Senator McCain said.
Together with Senator Flake and Senator Corker, Senator McCain is the third vocal Republican critic of Trump in the Senate. He was diagnosed with brain cancer in July.
Mr Trump has previously attacked Senator Flake as "weak" and "ineffective" and has derided Senator Corker's height while labelling him "incompetent".
White House spokeswoman Sarah Huckabee Sanders responded by saying voters in Arizona and Tennessee would likely not have supported Senator Flake or Senator Corker next year were they to have run.
"The voters of these individual senators' states are speaking in pretty loud volumes. I think that they were not likely to be re-elected and I think that that shows that the support is more behind this president than it is those two individuals," she said.
Corker takes aim
Mr Trump was making a rare trip to Congress on Tuesday to lobby for his tax reforms, but the president's efforts were overshadowed by an explosive new war of words pitting him against a top senator from his Republican Party.
The US president was due to attend the Senate Republican caucus lunch for the first time since his inauguration to rally support for passing a tax overhaul before year's end.
But attention instead has swerved to a brutal back-and-forth with Senator Corker, who charged in response to a Twitter attack from the president that Mr Trump is an "utterly untruthful" leader who "debases" the nation.
Senator Corker, an influential Republican who chairs the Senate Foreign Relations Committee and has emerged as an outspoken critic of the president, excoriated him earlier this month as dangerously impulsive and branded the White House an "adult day care centre".
He appeared to further antagonise Mr Trump when he told ABC early Tuesday he would like the president to stand clear of the debate over tax legislation and "leave it to the professionals" to finalise the plan.
Mr Trump rounded on Senator Corker in a series of tweets, and the war of words was on, playing out on television and social media in real time.
"Bob Corker, who helped President O give us the bad Iran Deal & couldn't get elected dog catcher in Tennessee, is now fighting Tax Cuts," Mr Trump tweeted.
"Same untruths from an utterly untruthful president," Senator Corker shot back.
"I don't know why he lowers himself to such a low, low standard and debases our country in the way that he does, but he does," Senator Corker went on to tell reporters in a Senate hallway, in a startling evisceration from within the commander-in-chief's own party.
"It's unfortunate that our nation finds itself in this place," he said, expressing regret for supporting Mr Trump's presidential bid and saying he would not vote for him again.
"He has proven himself unable to rise to the occasion.
"The constant non-truth telling, just the name-calling... I think the debasement of our nation will be what he'll be remembered most for, and that's regretful."
