In an interview with Renee Montagne, just before his final broadcast on NPR's Morning Edition Kasell reveals that he knew he would be in radio at a young age. He talks about how he hid behind the radio to fool passers-by into thinking they were listening to the radio when they in fact were hearing the young Kasell.

A native of Goldsboro, North Carolina, Kasell was a student of drama in high school, where one of his mentors was Andy Griffith, then a high school drama instructor. Although Griffith urged Kasell to pursue a career in theatre, Kasell took to radio more. During his time at the University of North Carolina at Chapel Hill, he helped launch local radio station WUNC with fellow student Charles Kuralt.

He worked as an announcer and DJ at a radio station in Goldsboro before moving to the Washington, DC area in 1965. He advanced to the position of news director at WAVA in Arlington, Virginia. As news director in Virginia, he hired Katie Couric as an intern one summer. He joined National Public Radio's staff as a news announcer for Weekend All Things Considered in 1975. He was the news announcer for NPR's Morning Edition from its inception in 1979 through 2009.

NPR launched its weekly news quiz Wait Wait... Don't Tell Me! in 1998, with Kasell as official judge and scorekeeper. The prize that Wait Wait... offers to its listener contestants is a recording of Kasell's voice for their personal telephone's answering machine or voice mail. Because this prize has been such a long standing tradition for the show, more than 2,000 people have Carl Kasell's voice on their home answering machine.

He is a member of the North Carolina Journalism Hall of Fame. In 1999, Kasell shared in the George Foster Peabody Award given to Morning Edition.

On November 23, 2009, National Public Radio announced that Kasell would retire from newscasting at the end of 2009. Kasell's final newscast aired on December 30, 2009. Kasell continues to appear as the official scorer of Wait Wait...Don't Tell Me! He will also continue to for NPR through visiting member stations and helping with fundraising.

During the August 7, 2010 broadcast of Wait Wait Don't Tell Me, host Peter Sagal announced that Carl Kasell had been voted into the National Radio Hall of Fame. The 2010 Induction Ceremony into the National Radio Hall of fame will be in Chicago, IL on November 6.