Growing up, Sharpe lived in Glennville, Georgia, with his grandmother and siblings, including his brother, former NFL tight end Shannon Sharpe. He attended Glennville High School, playing running back, quarterback and linebacker and was a member of the basketball and track teams.
As a wide receiver at the University of South Carolina, Sharpe set school records with 169 career receptions and 2,497 receiving yards and a since-broken record of 17 career touchdowns. He also set the school record for single-season receiving touchdowns with 11, which was broken in 2005 by Sidney Rice. Sharpe's #2 jersey was retired by South Carolina at the end of the 1987 regular season, making him only the second Gamecock to be granted this honor while still playing. His college coach and mentor, William "Tank" Black, left the Gamecocks to become a player manager and represented Sharpe throughout his professional career.
Sharpe was the first round #7 overall draft pick by the Green Bay Packers in 1988 and had an immediate impact on the team. In his rookie season he started all sixteen games and caught 55 passes. During his sophomore season, he led the league with 90 receptions, the first Packer to do so since Don Hutson in 1945, and broke Hutson's records for receptions and receiving yards in a season.
A few years later, in 1992, Sharpe and new quarterback, Brett Favre, teamed up to become one of the top passing tandems in the league. In the final game of the '92 season, Favre hooked up with Sharpe for his 107th reception of the season which broke the NFL's single-season receptions record, set by Art Monk in 1984. That season, Sharpe became one of only seven players in NFL history to win the "Triple Crown" at the receiver position: leading the league in receiving yards, receiving touchdowns, and receptions. Don Hutson (1936, 1941–44), Elroy Hirsch (1951), Pete Pihos (1953), Raymond Berry (1959), Jerry Rice (1990) and Steve Smith are the only other players to accomplish such a feat.
In the 1993 season Sharpe subsequently broke his own record, with 112 receptions; this also made him the first player to have consecutive seasons catching more than 100 passes. In 1994, his 18 touchdown receptions were the second most in league history at the time, behind only Jerry Rice's 22 in 1987.
Sterling Sharpe's tenure at wide receiver was cut short by a neck injury suffered during the 1994 season, ending a career in which he was named an All-Pro five times (1989, 1990, 1992, 1993, and 1994). Since he was unable to continue playing, and was not on the Packers team that won Super Bowl XXXI in 1996, his brother Shannon gave him the first of the three Super Bowl rings he has won, citing him as a major influence in his life by saying: “The two people who influenced me the most, good or bad, are Sterling and my grandmother. Everything I know about being a man, about football, everything I know about sports, pretty much in life, is because of those two people.”
Sharpe is currently an NFL analyst. After several years with ESPN, he moved to the NFL Network in time for the 2004 season, while continuing to do occasional work for ESPN as a color commentator. Starting in the 2006 season, he joined NBC's new NFL programming, serving as an analyst, along with Bob Costas, Cris Collinsworth, Peter King and Jerome Bettis. In 2007, he left his role at NBC and was replaced by Tiki Barber. He continues to work on the NFL Network mainly as an analyst on the program NFL Playbook.
His younger brother, Shannon, was one of the NFL's top tight ends from the 1990s to the early 2000s. Shannon retired in 2003 and once again followed in his brother's footsteps, becoming a sportscaster for the NFL pregame show on CBS, The NFL Today.