Educated at Northwestern University's Medill School of Journalism, Musburger began his career as a sportswriter for the Chicago American newspaper. Beginning in the late 1960s, Musburger worked in television, first for local stations in Chicago and Los Angeles. In late 1973, Musburger was doing play-by-play for CBS Sports.

By 1975, at CBS, Musburger went from doing the NFL play-by-play to rise to prominence as the host of the network's National Football League studio show, The NFL Today. By the late 1980s, Musburger was CBS' top sportscaster. He was now the main host to the NBA Finals, the NCAA Men's Division I Basketball Championship, college football, the Belmont Stakes, and others. He even hosted a New Year's Eve countdown for CBS. Musburger is generally regarded as the first broadcaster to apply the term March Madness to the annual NCAA Men's Division I Basketball Championship tournament.

Musberger joined ABC in 1990, and has called events such as Major League Baseball, NBA games, golf tournaments, the Indianapolis 500, Little League World Series, soccer games, college football, the NFL, and the Tour de France.

Starting in 2006, Musburger has called ABC Sports' college football prime time series, including the 2007 Rose Bowl, taking over for the recently retired ABC icon Keith Jackson.