He was the Republican Party candidate for the U.S. President in the 1964 election which he lost to Lyndon B. Johnson.

Hard to pigeonhole, he began as a reform Democrat, served as a friend and colleague of Joseph McCarthy to the bitter end (one of only 22 Senators who voted against McCarthy's censure), developed a deep friendship with President John F. Kennedy and a lasting dislike for Lyndon B. Johnson, whom he said "used every dirty trick in the bag", and Richard Nixon, whom he later called "the most dishonest individual I have ever met in my life" (though he was a key ally of Nixon during his administration).

Goldwater used to tell a joke about his brother Bob being told at a golf course, "You can't play here, this is a restricted course," to which he responded "I'm only half Jewish...is it all right if I only play nine holes?" In his autobiography he remarks, "The story got a big laugh, but the incident never occurred."

 The Johnson campaign ran a famous television commercial showing a scene in which a young girl is gathering daisies while a man performing a countdown is heard in the background; her frolicking is interrupted by the mushroom cloud of a nuclear explosion. Dubbed Daisy, it was meant to imply that Goldwater would start a nuclear war if elected. The commercial, which featured only a few spoken words of narrative and relied on imagery for its emotional impact, was one of the most provocative moments in American campaign history and is credited by many as being the birth of the modern style of negative television advertising. The ad ran only twice, and only in small local markets, but gained national attention through news coverage.