Cuomo was educated at Immaculate Conception School in Jamaica, Queens, and at The Albany Academy, a private university preparatory day school in Albany, New York, followed by Yale, where he earned an undergraduate degree, and Fordham, where he earned his Juris Doctor (J.D.) in 1995. He is a licensed attorney.

In 2001, Cuomo married Gotham magazine editor Cristina Greeven in a Roman Catholic ceremony in Southampton, New York. They reside in Manhattan with their three children. Cuomo also owns a home in Southampton.

From September 2006 to December 2009, he was the news anchor for Good Morning America. He was the primary reporter on breaking news stories, both in the U.S. and around the world, including dozens of assignments in some 10 countries. He covered the war on terrorism, embedded on multiple occasions in Pakistan, Afghanistan, and Iraq (where his convoy was hit by an IED). In the U.S., he covered shootings such as Virginia Tech, Fort Hood, and the Pennsylvania Amish school shootings, Hurricanes Katrina and Rita, the Sago Mine collapse, and the Minneapolis bridge collapse in August 2007. He anchored morning and evening coverage.

In February 2013, Cuomo moved to CNN to co-host its morning show. He made his debut on CNN as field anchor on the February 8, 2013, episode of Piers Morgan Tonight, covering the February 2013 nor’easter. In March 2018, while serving as the co-anchor of CNN’s morning show New Day, it was announced that Cuomo would move to primetime to host Cuomo Prime Time.

In October 2017, sister network HLN premiered a new documentary series hosted by the anchor, Inside with Chris Cuomo, which focuses on “stories affecting real people, in real towns and cities across America.”

In September 2018, he began hosting a two-hour weekday radio show “Let’s Get After It” on the P.O.T.U.S. channel on SiriusXM.

On August 13, 2019, in Shelter Island, New York, Cuomo threatened to throw a heckler down a flight of stairs at a bar, and chastised him with profanity-laced insults after the man called him Fredo, in reference to the fictional character from The Godfather novel and films. Cuomo told the man that the use of the name “Fredo” was tantamount to “the n-word” for Italian-Americans, which caused debate on Twitter about the assertion. Cuomo addressed the incident publicly, tweeting his appreciation to his supporters but acknowledging that he “should be better than what [he] oppose[s].”