After being selected as the fourth overall pick by the Cincinnati Bengals in the 2001 NFL Draft, Smith went on to play 14 seasons in the National Football League. When he became an unrestricted free agent in 2008, San Francisco swooped in and landed one of the top free agents on the market. A year later, Smith enjoyed the first Pro Bowl season of his career, which sparked a five-year stint of representing the 49ers on the all-star roster.

Smith's first Associated Press All-Pro came in 2011, when he was remarkably selected at two different positions, First-Team defensive tackle and Second-Team defensive end. He became the first NFL player ever to be named to the Associated Press' first and second team at different positions. Smith was also named Second-Team All-Pro at defensive tackle and defensive end, in 2012.

Smith has garnered great respect from the men he has shared the sidelines with, having twice won the Bill Walsh Award, which is voted on by the coaches and awarded to the team's Most Valuable Player. Along with RB Frank Gore and LB Patrick Willis, the three are the only two-time winners of the award in team history. Smith is also a two-time recipient of the Len Eshmont award, which honors the team MVP as selected by the players. A four-time recipient of the Hazeltine Iron Man Award, given to the most courageous and dedicated defensive player as selected by the defensive coaching staff, he was also presented the Perry/Yonamine Unity Award and Ed Block Courage Award during his time with the 49ers.

During his career, Smith started 217 of 221 games played, including a streak of 185 consecutive starts from his rookie season through December of 2012. He finished his career with 1,370 tackles, 87.0 sacks, 16 forced fumbles, 10 fumble recoveries, three interceptions and 30 passes defensed. Smith posted at least 5.0 sacks in 12 of his 14 seasons played and is one of 13 players, since sacks became an official statistic in 1982, to register 5.0-or-more sacks in 12-or-more seasons. With 6.5 sacks during the 2013 regular season, Smith became just the 20th player in NFL history to register at least 5.0 sacks in 11 separate seasons. He also posted at least 6.0 sacks in four consecutive seasons (2008-11), becoming just the third player in 49ers history to do so.