He painted the US President as a threat to democracy who misleads the public with his tweets and fosters division with his rhetoric.
And he conjured up the gaze of future generations, pledging that he would not be "complicit or silent" in the face of Trump's provocations.
"We must stop pretending that the degradation of our politics and the conduct of some in our executive branch are normal," Flake said on the Senate floor.
"They are not normal. Reckless, outrageous and undignified behaviour has become excused and countenanced as 'tell it like it is' when it is actually just reckless, outrageous and undignified.
"And when such behaviour emanates from the top of our Government it is something else. It is dangerous to a democracy."
Trump, the Senator went on, was someone who called "fake things true and true things fake".
He was "indulging in or even exalting our worst impulses" and undermining America's standing abroad.
Flake added: "When the next generation asks us 'why didn't you do something, why didn't you speak up' what are we going to say? Mr President, I rise today to say enough."
While this speech will not trigger Trump's fall, the question emerging in Washington is whether it is a turning point in the civil war engulfing the Republican Party.
Flake - a frequent critic of Trump - was not the party's first senator to speak out against the US President today.
Bob Corker, the Senator for Tennessee, had hours earlier lambasted Trump for being an "untruthful" leader whose legacy would be the "debasement" of his country.
He said Trump had "proven himself unable to rise to the occasion" of being President and was a bad role model for children.
The intervention of both men on a day designed for unity, with Trump lunching with Republican Senators to discuss tax reform, equals the strongest internal criticism yet.
It follows more than a week of negative headlines about Trump's handling of a phone call to the widow of a fallen US soldier killed in Niger.
First he claimed former President Barack Obama never called war widows, which was proved untrue. Then he denied saying the soldier "knew what he was getting into" in his call, contradicted by the White House. Eventually he was publicly rejecting the widow's own claim he forgot the fallen American's name.
Flake and Corker's decision both to speak out against "untrue" statements by the President has been billed as an 'enough is enough' moment.
But the real significance of their interventions must be understood in the context of the 2018 midterms.
Flake and Corker were both up for re-election next year. Both have now announced they are standing down.
The pair had triggered the ire of the US President after criticism in recent weeks and - more worryingly, perhaps - the attention of his most faithful attack dog.
Bannon, credited with turning around Trump's campaign last year, has left the White House and declared a "season of war" on the Republican establishment.
He is lining up rival candidates to challenge those Senators up for re-election for their party's nomination, threatening the careers of some senior figures.
The reason for his and Trump's fury is the perceived failure of Republican Senators to help Trump pass major legislation - something still yet to be achieved.
Both Bannon and Trump had publicly backed Kelli Ward, the woman challenging Flake to be the Republican candidate for Arizona, before he pulled out today.
Corker, whose Twitter fights with the President have included calling the White House an "adult day care centre", has already announced he will not seek another term.
In the age of the political outsider, establishment Republicans are reading the ruins and deciding that they have little chance of keeping their seats - especially in the face of such an unrepentant onslaught from Bannon.
So while Flake's scathing speech will be seen as a blow for Trump, it should also be read as an acceptance of the moderate Republican wing's weakness.
Nine months into the Trump presidency, his support base appears to be holding up so much that Senators who have lost his backing are giving up hope of re-election.
More could follow through the door, with half a dozen sitting Republicans facing a similar situation. And for every one that does, Trump's hold over his party will grow a little stronger.
