The son of Boston Globe sportswriter Will McDonough, Sean McDonough graduated from Syracuse University in 1984. It was in Syracuse where McDonough began his broadcasting career in 1982 as the play-by-play announcer for the Syracuse Chiefs of the International League. Four years after graduating from Syracuse, he began broadcasting Boston Red Sox games on WSBK-TV (Channel 38) in Boston with former Red Sox catcher Bob Montgomery. McDonough continued to announce local Red Sox broadcasts, moving over the years to different local stations including WFXT (Channel 25), WABU (Channel 68) and WLVI (Channel 56). Over the years, his other obligations began to interfere with his announcing of Red Sox games, and he seemed to call fewer and fewer each season. In 1996, he was teamed with former Red Sox second baseman Jerry Remy, with whom he worked for nine seasons before McDonough was replaced completely in 2005 by Don Orsillo.

McDonough was an Ivy League football announcer for PBS. He was a sideline reporter from 1984–85, and a play-by-play announcer from 1986–87.  He began work for CBS Sports in 1990, where he broadcast college basketball (including 10 NCAA tournaments), college football (including the prestigious Orange Bowl game), the College World Series, the NFL, US Open tennis, three Winter Olympics (bobsled and luge in 1992 and 1994 and ice hockey in 1998), and golf (including four Masters and PGA Championships).  Outside of New England, he is probably best remembered for his time as CBS' lead baseball announcer, a role in which he was teamed with Tim McCarver. In 1992, at the age of 30, he became the youngest man to announce the national broadcast (and all nine innings of all of the games played) of the World Series. Coincidentally, that particular record would be broken four years later by Fox's 27-year-old Joe Buck, the son of the man McDonough replaced on CBS, Jack Buck.

Since 2000, McDonough has announced baseball, college basketball, college football, and NHL and NCAA hockey for ABC and ESPN. Specifically, McDonough announces many Big East college football and basketball events. He also contributes to ESPN's coverage of the U.S. Open and British Open golf tournaments