The home state of former Republican nominees Barry Goldwater and John McCain has voted Republican in 15 of the past 16 elections, breaking only to support Bill Clinton in 1996.
Other conservative newspapers have also broken with decades of tradition to endorse Clinton, including the Cincinnati Enquirer and the Dallas Morning News.
Publishing scathing criticism of Trump, the national paper urged readers to oppose a candidate it said is "dangerous" and "unfit for the presidency".
The publication goes on to criticize Trump's many controversies on the campaign trail - many of which have prompted critics to question whether he is fit to be commander-in-chief.
The newspaper, which had never endorsed a Democrat for president over a Republican, said it made a decision to back Clinton and not Trump because it believes the 2016 GOP nominee "is not a conservative and he is not qualified".
The Republic's rejection of Trump makes it the latest newspaper with a history of endorsing Republican candidates to turn on the party's nominee.
The extensive editorial concluded that while Trump's political pandering isn't worth jack, the deep public discontent that his campaign has unearthed is.
The Arizona Republic, the state's largest newspaper, has never endorsed a Democrat for president - until now. "This year is different", the paper wrote in its endorsement this week.
As it turns out and especially so, amidst such unsettling fracturing of mainstream media, newspaper editorial endorsements still can pack a punch. Meanwhile, the Houston Chronicle, typically pretty conservative, wrote that Trump is a "danger to the Republic", and that "his erratic temperament, his dodgy business practices, his racism, his Putin-like strongman inclinations and faux-populist demagoguery, his contempt for the rule of law, his ignorance", disqualify the businessman as a presidential candidate.
"Well, it's been insane around here", said Phil Boas, who runs the paper's editorial page.
Warner's decision not to support his party's nominee, Donald Trump, is meant to send a signal in the five-term senator's battleground home state and beyond that mainstream, security-minded Republicans should side with Clinton.
These things simply do not happen in American politics, and they are happening now because Trump is risky in a way that transcends policies and partisanship.