Safire, who was 79, had been diagnosed with cancer and died at a hospice in Maryland, assistant Rosemary Shields said. She declined to specify the type of cancer Safire had or say when he had been diagnosed.
Safire spent more than 30 years writing on the Op-Ed page of The New York Times. In his "On Language" column in The New York Times Magazine and 15 books, Safire traced the origins of words and everyday phrases such as "straw-man," "under the bus" and "the proof is in the pudding."
Safire penned more than 3,000 columns, aggressively defending civil liberties and Israel while tangling with political figures. Bill Clinton famously wanted to punch the curmudgeonly columnist in the nose after Safire called his wife "a congenital liar."
Shields said: "Not only was he brilliant in language and assessing the nuances of politics, he was a kind and funny boss who gave lots of credit to others."
As a speechwriter in the Nixon White House, Safire penned Vice President Spiro Agnew's famous phrase, "nattering nabobs of negativism," a tongue-in-cheek alliteration that Safire claimed was directed not at the press but at Vietnam defeatists.
Safire also wrote several novels and served as chairman of the Dana Foundation, a philanthropy that supports brain science, immunology and arts education.
Along with George Will and William F. Buckley Jr., Safire's smooth prose helped make conservatism respectable in the 1970s, paving the way for the Reagan Revolution.
Safire was a pioneer of opinionated reporting. His columns were often filled with sources from Washington and the Middle East, making them must-reads for Beltway insiders.
Author Eric Alterman, in his 1999 book "Sound and Fury: The Making of the Punditocracy," called Safire an institution unto himself.
"Few insiders doubt that William Safire is the most influential and respected pundit alive," Alterman wrote.
Safire's scathing columns on the Carter White House budget director Bert Lance's financial affairs won him the Pulitzer Prize for commentary in 1978; in 1995 Safire was named to the Pulitzer board.