Cuomo's early career in journalism included appearances related to social and political issues on CNBC, MSNBC, and CNN. Cuomo was a correspondent for the Fox News Channel and Fox Broadcast Network's Fox Files, where he covered a wide range of stories focusing on controversial social issues. He also served as a political policy analyst for Fox News Channel.

At ABC and as co-anchor of 20/20, Cuomo's most recent long-form coverage includes a look at heroin addiction. His year-long coverage revealed the heroin addiction affecting suburban families. Other work has included coverage of the Haiti earthquake, child custody, bullying, and homeless teens. Policy change has come after Cuomo's undercover look at for-profit school recruiters, leading to an industry clean-up; and Cuomo's tip from a BMW owner led to a recall of over 150,000 affected models.

From September 2006 to December 2009, Cuomo was the news anchor for Good Morning America. Cuomo was the primary reporter on breaking news stories, both at home 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). At home, 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. Cuomo anchored morning and evening coverage.

Cuomo maintains a website, "Cuomo on the Case", where he takes questions, and which acts as a platform for his reporting and discussion on a number of issues. Cuomo had two weekly digital programs on ABC News, The Real Deal and Focus on Faith, that discussed matters of spirituality. He also appeared with Father Edward Beck on ABC News Now, the network's 24-hour digital outlet.

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. Cuomo is the co-anchor of CNN's morning show New Day, and continues to report on major events and breaking news across the network.

Cuomo has received multiple Emmy Award nominations. Notably, Cuomo's Good Morning America profile of the 12-year-old poet Mattie Stepanek was recognized with a News Emmy, making Cuomo one of the youngest correspondents to receive a News Emmy in network news history. Cuomo has been awarded Polk and Peabody Awards for team coverage. His work has been recognized in the areas of breaking news, business news, and legal news, with the Edward R. Murrow Award for breaking news coverage, a Loeb Award for business reporting, and the American Bar Association Silver Gavel Award for investigating juvenile justice.