Keith Jackson, known to many as "the voice of college football," was born in Roopville, Georgia and still has a distinct Southern accent. He attended Washington State University and was a member of the Alpha Tau Omega fraternity. It was here that his career as a broadcaster began. In 1967, he became part of ABC's coverage of NCAA college football. That season, he broadcast a contest between the University of Southern California, then ranked Number 1 in the country, and their intracity arch-rivals the University of California at Los Angeles, ranked Number 2. USC won the game, beating UCLA 21-20, and took the championship of the league then known as the Pacific Eight Conference, now the Pacific Ten. Jackson would later call this game (one of several to become known as the "Game of the Century") the greatest that he had ever broadcast. USC went on to defeat Indiana University in the Rose Bowl and claim the National Championship.

In 1970, Jackson was chosen to be the first play-by-play announcer on Monday Night Football, performing this role only during the program's first season. In 1971, he was supplanted in that role by Frank Gifford (who was at the time, considered by ABC to have more star power than Jackson), who had been hired away from rival CBS.

Afterwards, his association with football was entirely with the collegiate game, except from 1983 to 1985, when he served as ABC's lead voice for the ill-fated United States Football League. Although he's best known for commentating college football games, Jackson has announced numerous other sports for ABC throughout the 1970s and 1980s, including Major League Baseball, NBA basketball, boxing, auto racing, and the Olympic Games. Jackson also served as the anchor for ABC's coverage of Super Bowl XXII in 1988. Keith Jackson's most notable non-college football assignment was arguably, his calling (alongside Tim McCarver) of the now famous 16-inning long sixth game of the 1986 National League Championship Series between the New York Mets and Houston Astros.

Jackson was involved in the ABC coverage of the 1972 Summer Olympics and continued to contribute even when an attack by Palestinian terrorists turned the coverage away from being primarily sports coverage to that of a news event. Over the years, he has been paired with a wide variety of commentators, including perhaps most notably University of Arkansas athletic director Frank Broyles, a former football coach, and pro football legend Bob Griese. For many years, he was assigned by ABC to the primary national game of the week. He is generally considered by many college football fans to be the "voice of college football"; his expressions such as "Whoa, Nellie!" and "Fum-BLE!" are often the subject of attempts at comedic imitation.

Jackson announced his retirement from college football announcing at the end of the 1998 season and his intention to live full-time at his home in California, with his last broadcast to have been the 1999 Fiesta Bowl for the National Championship between Tennessee and Florida State. He rescinded this decision the following fall and began to do a more limited schedule of games, teamed with Dan Fouts, almost exclusively sticking to venues on the West Coast, closer to his current home in British Columbia. Jackson decided to retire for good on April 27, 2006, with a phone call to the New York Times. "I'm finished with play-by-play forever," he stated.

Jackson has had a minor career as an actor, either playing himself (as on a famous episode of Coach) or a sportscaster like himself, as in The Fortune Cookie (1966). He has also appeared in and/or narrated several sports documentaries. His play-by-play of the 1977 World Series is used in the background of the Spike Lee film, Summer of Sam (1999). Jackson once parodied his broadcast persona for a Bud Light beer commercial. His latest commercial efforts are for Shoney's, a chain of family-style restaurants well-known in the Southeast, especially in his native Georgia, and for recent "the legend of Gatorade" ads. He also participated in blending paid commercial advertisements and bona-fide sports coverage by acknowledging a joking reference to his endorsement of Gatorade during the 2006 Rose Bowl, an apparently-free product placement of Gatorade during live coverage. (Pepsi is the sponsor of another BCS game the Fiesta Bowl.) In 2006, he also was shown in a commercial for Ice Breakers' Ice Cubes with Hilary Duff, Haylie Duff, and Joey Lawrence, contributing his famous line "Whoa, Nellie!"