Safire was one of the leading critics of the Bill Clinton administration. Especially Hillary Clinton was often the target of his ire. He caused a mild tempest when he called her a "congenital liar".

He is also a consistent and avowed partisan in the defence of the state of Israel.

In 1978, he won the Pulitzer Prize for distinguished commentary.

Before he became a journalist, Safire was a speechwriter for Richard Nixon and Spiro Agnew; he wrote Agnew's phrase "nattering nabobs of negativism." Earlier still, he was a public relations executive.