The Broward County-based Sun-Sentinel's decision comes as Florida's 99-delegate, winner-take-all March 15 primary approaches.
A win there is particularly key to Rubio, who has fallen behind Republican front-runner Donald Trump and Texas Sen. Ted Cruz in the race for delegates. A Monmouth University poll released Monday
shows Rubio is strongest in the southern part of the state.
But the Sun-Sentinel, which had initially backed Jeb Bush in the GOP primary, lambasted Rubio, writing that he "has almost no experience and has done little but run for office," and criticizing his missed Senate votes.
"Because Rubio has failed to do his job as a senator, broken the promises he made to Floridians and backed away from his lone signature piece of legislation on immigration, we cannot endorse him for president," the newspaper wrote.
It wasn't just Rubio. The newspaper said he, Trump and Cruz are all "unqualified to be president."
"Ohio Gov. John Kasich is the best of the bunch, but if you measure a candidate by the caliber of his campaign, Kasich's lack of traction and organization make a vote for him count for little," the paper wrote.
Rosemary O'Hara, the newspaper's editorial page editor, said in an interview with CNN's Brooke Baldwin that it's the first time the Sun-Sentinel hasn't endorsed a presidential candidate.
"We're disappointed with (Rubio). We endorsed him when he ran for Senate believing that he was an agent of change and he would follow through, but as soon as he got to Washington, he started running for president," she said. "We haven't seen much of him since he went to Washington."
The Sun-Sentinel isn't the only newspaper editorial board suggesting Republican presidential candidates are unqualified. The Arizona Republic's is taking aim specifically at Trump.
A recent Republic editorial
suggested GOP primary voters have a moral obligation to vote against the mogul.
"History will be kind to Republicans who denounce Donald Trump. It is especially important to do so now -- when Trump's megalomaniacal pursuit of the GOP nomination looks stronger than ever and some are calling his success inevitable."
The piece is notable because two prominent Arizona Republican public figures -- former Gov. Jan Brewer and Maricopa County Sheriff Joe Arpaio -- are backing Trump.