He was born in New York City to Jewish parents Benjamin and Helen. He grew up in Manhattan and graduated from the Bronx High School of Science in 1960. He obtained a B.A. degree from the University of Wisconsin—Madison in 1964, where he served as editor-in-chief of the Daily Cardinal. He graduated with an LLB degree from the Yale Law School in 1966, where he was a Note and Comment editor of the Yale Law Journal. He also served as a speechwriter for Senator Robert F. Kennedy.

Greenfield lives in New York and Salisbury, Connecticut. He was married to Carrie Carmichael until their divorce in February 1993. They have one daughter, Casey, and one son, David. On April 24, 1993, he married Karen Gannett, from whom he is now divorced. He appeared on the Imus in the Morning show on August 11, 2008 and gave a very negative evaluation of the Beijing 2008 Olympics opening ceremony, calling it a "chilling" display. He also stated that the ceremony was shot in a similar way to the one held in Berlin, Germany in 1936.

Over the course of his career he has reported primarily on domestic politics and the media, and occasionally on culture. He appeared on the Firing Line television program in 1968. He served as media commentator for CBS News from 1979 to 1983 and as Political and Media Analyst for ABC News from 1983 to 1997, often appearing on the Nightline program. He served as a Senior Analyst at CNN from 1998 to 2007. On 1 May 2007, Greenfield returned to CBS News to serve as Senior Political Correspondent. He is currently doing political commentary on NBC Nightly News. Mr. Greenfield has been host of the national public television series "CEO EXCHANGE", featuring in-depth interviews with high-profile chief executive officers, for five seasons.

He has also written or contributed to eleven books, and written for Time Magazine, The New York Times, and Slate.com.

Greenfield is the recipient of three Emmy Awards, two for his reporting from South Africa (1985 and 1990) and one for a profile of H. Ross Perot (1992).