Flake denounced the "complicity" of his own party in what he called an "alarming and dangerous state of affairs" under Trump, blaming the President for setting the tone. In his speech, Flake assailed a "flagrant disregard for truth or decency" and attacked a "regular and casual undermining of our democratic norms."
"When such behavior emanates from the top of our government, it is something else: It is dangerous to a democracy," Flake said.
Flake said he did not enjoy sparring with Trump. "If I have been critical, it's not because I relish criticizing the behavior of the President of the United States," Flake said. "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."
Flake went on to say that history would judge those who did not speak up. "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 decision not to seek re-election means Flake joins retiring Tennessee Sen. Bob Corker as an outspoken critic of Trump with nothing to lose in the year before 2018's midterm elections.
The White House suggested it was time for Flake to retire.
"Based on the lack of support he has from the people of Arizona, it's probably a good move," press secretary Sarah Sanders said during the daily press briefing.
In his first interview after speaking on the Senate floor, Flake refused to comment on Sanders' remarks but outlined his issues with the President to CNN's Jake Tapper.
"It's difficult to move forward in a Republican primary if you have been critical of any of the behavior that's gone on," Flake said on CNN's "The Lead." "We Republicans certainly can't countenance that kind of behavior. We ought to stand up and say 'This is not right. This is not us. This is not conservative.'"
Flake's political fortunes suffered as a result of his long-running feud with Trump -- which included an anti-Trump book published by Flake in the summer. Private polls conducted by Republican and Democratic groups in Arizona, sources with those groups said, showed him on track to lose badly in next August's Republican primary to challenger Kelli Ward.
His retirement is a double-edged sword for Trump's White House: It opens the door for Flake to be replaced with a more supportive Republican. But it also provides an opportunity for Democrats to pick it up.
And it turns Arizona -- once a Republican stronghold but increasingly competitive in recent elections -- into perhaps the most important state in the 2018 midterms, with Flake's seat now open and questions looming about Sen. John McCain's long-term prognosis as he is treated for brain cancer.
McCain and Corker were both in attendance of Flake's Senate floor speech Tuesday and gave him a standing ovation at conclusion of his remarks -- as did Wyoming Republican Sen. John Barrasso.
"One of the greatest people I've served with," Corker said after the speech, describing Flake and adding later, "He's what I would call a real conservative."
Corker said Flake told him about his decision after the lunch among Republican senators earlier Tuesday.
When asked what it said about the Senate that Flake said he couldn't fit into the current Republican party, Barrasso said that is up to every senator to decide.
"Every senator speaks for themselves. I continue to be very privileged to represent the people of Wyoming and hope to continue to do that in the future," Barrasso said.
Sen. John Cornyn, the second ranking Republican in the chamber, said it is "a very sad day" and GOP Sen. Susan Collins of Maine, who recently decided to skip a run for governor and stay in the chamber, said she was "incredibly disappointed" by Flake's decision.
Democratic Sen. Tim Kaine of Virginia left the floor in tears following Flake's speech, calling it "depressing."
"When someone as good and decent a person as Jeff Flake does not think he can continue in the body, it's a very tragic day for the institution," Kaine said.
The fight with Trump
Flake's congressional career came full circle. He began in the House in 2001 as an outsider raging against earmarks. By the time he launched his Senate campaign in 2012, he was a favorite of conservative groups like the Club for Growth, which had grown in power and influence on Capitol Hill. Now, Flake is again on the outs, with Trump's populist policies taking hold with Republican voters.
In politics and personality, Trump and Flake have little in common.
Flake, a Mormon from the tiny town of Snowflake, Arizona, is polite and introspective. He journals regularly and, while in the House, regularly emailed his thoughts on travel and policy to a small, private list of family and friends.
He's long expressed major policy differences with Trump -- particularly on trade. In August he called Trump's decision to withdraw from the Trans-Pacific Partnership "a big mistake which will haunt us for a long time." He has also defended the North American Free Trade Agreement, warning that its cancellation would badly damage the economies of border states like Arizona.
Flake refused to endorse Trump in the general election, and then three months ago published a book sharply critical of Trump titled "Conscience of a Conservative: A Rejection of Destructive Politics and a Return to Principle."
In the book, Flake worries about "the strange specter of an American president's seeming affection for strongmen and authoritarians." He also called now "one of the more reckless periods of politics in our history." And he questioned whether Republicans having won the House, Senate and White House in 2016 was worth the cost of putting "at risk our institutions and our values."
"We shouldn't hesitate to speak out if the President 'plays to the base' in ways that damage the Republican Party's ability to grow and speak to a larger audience," Flake wrote.
Trump, meanwhile, had long plotted to oust Flake.
He told supportive Republicans in Arizona prior to the 2016 election that he would spend $10 million of his own money to see that Flake is unseated in the primary.
His White House has been in regular contact with State Treasurer Jeff DeWit, former state party chairman Robert Graham and other Republicans about the race. Former Trump White House chief strategist Steve Bannon backed Ward even while working in the White House, and Robert Mercer, the GOP mega-donor and close Bannon ally, has given $300,000 to a pro-Ward super PAC.
At an August campaign rally in Phoenix, Trump huddled backstage with DeWit, Graham and Rep. Trent Franks. Two sources familiar with the meeting told CNN it was focused on ousting Flake -- who Trump calls "the flake."
The fight in Arizona
Flake's decision opens the door for Ward, a conservative former state senator who many Arizona Republicans see as a controversial and problematic general election candidate. But now that the seat is open, Republicans will try to recruit another candidate into the race.
As Republicans look for another candidate to enter the primary, all eyes are now on DeWit, who was the Trump campaign's chief operating officer, one Arizona Republican operative said.
"The deal is, DeWit has two days to grab the ring. It's his if he wants it, but he's got to move quick. If he wants it, everyone steps out the way. If he doesn't, chaos ensues," the operative, who asked for anonymity to frankly discuss the state of play, said.
DeWit "definitely has the President's support" whereas others would have to earn it, the operative said. If DeWit doesn't run, the operative said, potential candidates include Reps. Paul Gosar and David Schweikert, as well as Christine Jones, a 2016 congressional candidate and former GoDaddy executive. Republicans have also eyed Rep. Martha McSally, and Rep. Trent Franks has been involved in conversations about ousting Flake.
The winner is likely to face Democratic Rep. Kyrsten Sinema.
This story has been updated and will update with additional information.