Playing as a true freshman, Spence was a starter in Miami’s final eight games, and ranked third on the team with 62 tackles to go along with 7.5 tackles for loss, and a pair of sacks. He was named to College Football News′ All-Freshman first team, as well as Rivals.com′s 2008 Freshman All-America team. Four weeks into the 2010 season, Spence had team-highs in tackles and tackles for loss in only four games. At the end of the 2011 season, Spence earned first-team All-ACC recognition for the 2011 season. The senior captain, who tied for fifth place in the Atlantic Coast Conference with 106 total tackles in 2011, ended the year second among all NCAA players with 47 career tackles for loss, including 14.0 in 2011. A semifinalist for the Butkus Award, Spence averaged 9.64 tackles per game and 1.27 tackles for loss per game in 2011. He finished the season with three sacks, one pass break-up and one forced fumble.
Professional career
Pittsburgh Steelers
The Pittsburgh Steelers selected Spence in the third round of the 2012 NFL Draft. He was the 11th linebacker selected in 2012. On May 29, 2012, the Pittsburgh Steelers signed Spence to a four-year, $2.70 million contract. He suffered a serious knee injury during the preseason and was declared out for the entire 2012 season. On August 25, 2013, the Steelers placed Spence on the Reserve/Physically Unable To Perform List. Three weeks after being taken off of the PUP list, the Steelers placed Spence on injured reserve, ending his injury-ridden 2013 season. Sean Spence finished the 2014 season with 53 tackles and 1 sack for the Steelers, finishing with a record of 11–5 and winning the AFC North Division. Spence, who missed one game and didn't finish two due to hamstring injuries, had 37 tackles and a sack as the Steelers completed the 2015 regular season with a 10–6 mark. The Steelers won their first round playoff game against the Cincinnati Bengals before dropping the next to Denver.
Tennessee Titans
On March 16, 2016, the Tennessee Titans signed Spence to a one-year, $2.5 million contract, reuniting him with former Steelers defensive coordinator Dick LeBeau. Spence finished the 2016 season with 50 tackles, three sacks, and one forced fumble.
Indianapolis Colts
On March 19, 2017, Spence signed a one-year, $3 million contract with the Indianapolis Colts. On September 2, 2017, the Colts released Spence as part of the final roster cuts. He was re-signed on September 13, 2017. He was released again on October 3, 2017.