Five Republican lawmakers — including Michele Bachmann, a Minnesota congresswoman and former Republican presidential hopeful — recently charged that Huma Abedin is an infiltrator for the Muslim Brotherhood, an influential and controversial Islamic movement.
Abedin is also married to Anthony Weiner, the disgraced Democratic congressman who's staunchly pro-Israel.
Such baseless suggestions disgrace Congress, McCain said as he took to the Senate floor on Wednesday to defend Abedin's honour.
"When anyone, not least a member of Congress, launches specious and degrading attacks against fellow Americans on the basis of nothing more than fear of who they are and ignorance of what they stand for, it defames the spirit of our nation," McCain said.
"And we all grow poorer because of it."
Bachmann and four other Republican legislators — Trent Franks, Louis Gohmert,Tom Rooney and Lynn Westmoreland — recently alleged that Abedin and members of her family are linked to the Muslim Brotherhood. They demanded a State Department investigation in June into whether Congress has been infiltrated by the group, and have suggested Abedin should be stripped of her security clearance.
McCain scoffed at the allegations contained in their lengthy letter to the State Department and other federal departments, saying his fellow Republicans' accusations are completely unsubstantiated.
"I understand how painful and injurious it is when a person's character, reputation and patriotism are attacked without concern for fact or fairness," he added.
Since his unsuccessful run for president in 2008, largely remembered for his ill-fated pick of Sarah Palin as his running mate, the Arizona senator has been a colourful, unpredictable and occasionally irascible presence on the American political stage.
Once adored as a "maverick" unafraid to stand up to his own party under George W. Bush, he was convinced by Republican strategists in 2008 to choose Palin rather than his first pick, independent Sen. Joe Lieberman, a moderate and former Democrat.
McCain was said to have been personally wounded by his subsequent loss to Obama. He's since been one of the president's harshest critics, even saying this week that Obama's first term has been "the worst thing I've ever seen."
But he's also praised Obama on occasion, continues to spar with members of his own party publicly and privately and last summer famously disparaged Tea Party adherents as "hobbits."
At best, he's only a part-time maverick now. This week, he voted against Democratic legislation calling for the type of sweeping campaign finance reform that he's long championed.
In 2010, with mid-term elections on the horizon, he also voted against the so-called DREAM Act —a bill that would ease the path to citizenship for illegal immigrants — despite having been one of the bill's sponsors for five years.
Nonetheless, McCain is still cut from a different cloth than many contemporary lawmakers, said Stephen Hess of the Washington-based Brookings Institution. That's partly because he isn't a lifelong politician, and because he came of age during a period when legislators didn't uniformly speak in party talking points.
"We tend to criticize the coterie of senators today as coming out of a cookie cutter, and he certainly doesn't," said Hess, a former aide to president Richard Nixon.
"I've heard people ask: 'Where are the Bob Doles, the Pat Moynihans, the people with a willingness to speak up, sometimes against their own party?'" Hess said. "That's where McCain fits in."
Age and its inherent wisdom are probably behind McCain's willingness to vent spleen when his fellow Republicans anger him, Hess added.
"Lack of ambition is probably also at play now. He's not ambitious for the next political office, the step up, because there isn't one anymore, not after his run for president," he said.
"And while there are lots of legislators at the bottom who are willing to speak up, McCain is one of the few at the top who has little to lose."
Bachmann, however, wasn't backing down from her allegations on Wednesday, saying her letter to various federal departments has been "distorted."
"I encourage everyone, including media outlets, to read them in their entirety. The intention of the letters was to outline the serious national security concerns I had and ask for answers to question regarding the Muslim Brotherhood and other radical groups' access to top Obama administration officials."