Salisbury became USC's starting quarterback midway through the 1982 season, which they ended with a record of 8-3; NCAA sanctions prevented them from playing in a bowl game. In 1983 the Trojans, still under sanctions, fell to a record of 4-6-1, their first losing season in 22 years. Salisbury suffered a season-ending injury early in the 1984 season, but was on the team as USC won the Rose Bowl over Ohio State. In his 1985 senior year, Salisbury was the main quarterback through a 6-5 campaign, but lost the starting job to Rodney Peete before they fell to Alabama in the Aloha Bowl. Salisbury finished his USC career as the school's all-time leader in pass completions and yards gained, breaking marks previously held by Paul McDonald; both records were later broken by Peete. Salisbury was also second in pass attempts and fourth in touchdowns. He also ranked fourth in USC history in total offense, trailing Charles White, Marcus Allen and Jimmy Jones.
After getting his start on the Comedy Central show BattleBots, Salisbury went on to become an NFL analyst on ESPN, appearing on SportsCenter and NFL Live. In 2004, Salisbury was offered a job with the Arizona Cardinals by his former coach and fellow co-worker at ESPN, Dennis Green, to become their new quarterbacks coach. Salisbury pondered for weeks, but eventually declined and stayed on with ESPN. Salisbury was hired as a consultant for the 2005 remake of The Longest Yard. On the set, Salisbury taught Adam Sandler proper quarterback mechanics, cadences, and footwork. Sandler later offered Salisbury a role in the 2006 film he produced, The Benchwarmers. On May 9, 2006, Salisbury began broadcasting on ESPN Radio 1000, Chicago with Steve Rosenbloom. He also did guest spots on the ESPN Classic comedy program Cheap Seats, where he provided his signature breakdowns of the action in a more comedic manner. He has covered for Mike Golic on Mike and Mike in the Morning. In 2007, Salisbury's No. 12 football jersey was retired at his alma mater, Orange Glen High School, an honor no other person in school history has ever received. "I can't believe I'm having my number retired like John Elway, Marcus Allen, Larry Bird or Magic Johnson," Salisbury said. "In my own little world, I will always cherish being the first at my high school to be honored like this." After ESPN, Salisbury worked briefly for OPENSports.com and KRLD-FM 105.3 The Fan, the CBS Radio affiliate in Dallas. On September 25, 2009, Salisbury provided the color commentary for the Lingerie Football League presentation of Friday Night Football. On October 20, 2010, it was announced Salisbury would host a pilot for a sports comedy talk show called Inside Sports: News You Can Almost Trust. The show aired on Versus in January. Producer Mark McClure called the show "ESPN meets Comedy Central's Daily Show with some SNL skits, too. Sean will be our Jon Stewart." After the pilot aired the show was retooled as a more serious Inside Sports Unleashed, which began taping on May 12, 2011. On September 9, 2013, Salisbury became part of the Yahoo! Sports Radio network lineup as co-host of "The War Room" with John Granato airing from 3:00 pm to 7:00 pm ET daily. The program remained when Yahoo! Sports Radio was renamed SB Nation Radio in 2016. He became the host of The Sean Salisbury Show on beIN Sports on April 17, 2017. In June 2018, he left BeIn Sports and SB Nation Radio to become the afternoon-drive host at Houston radio station KBME Sportstalk 790. On March 25, 2019, KBME moved him to morning drive, replacing Josh Innes.
