Smith is a native of Norfolk, Virginia, where he graduated from Booker T. Washington High School. Following an all-state high school career, Smith accepted an athletic scholarship to Virginia Tech. Known as “The Sack Man” as a Hokie, Smith finished his college career in 1984 as the most honored player in Hokie history. Foreshadowing his future success in pursuing quarterbacks in the NFL, he had a career total of 71 tackles behind the line of scrimmage, for losses totaling 504 yards. Smith had 46 career sacks, including an NCAA-leading 22 during a junior season in 1983 that saw him named First-team All-America by the AFCA (Coaches) and Newspaper Enterprise Association. In 1984, Smith capped off his tenure in Blacksburg with the Outland Trophy, given to the nation’s top lineman, and a consensus selection to the All-America Team. His accomplishments at Virginia Tech earned him a spot in the Virginia Tech Sports Hall of Fame.

Following this stellar collegiate career, Smith was drafted by the Buffalo Bills with the first pick of the 1985 NFL Draft. (Concurrently he was also selected by the Baltimore Stars in the 1985 USFL Territorial Draft but spurned the United States Football League advances.) After a rookie season in which his poor training habits limited his effectiveness, inspiration from teammate Darryl Talley and finding love with a college counselor whom he eventually married inspired him to improve his game. He quickly became known as a sack specialist, with 15 in 1986 and a personal season-best 19, just three short of the then-NFL record of 22, in 1990. By 1989, Smith, in notching his 52nd sack, had already become the Bills’ all-time sack leader, claiming a team record that he was to raise 119 times over the years. Some conjecture that his 171 sacks in Buffalo set a standard that “may be unreachable” for future Bills.

In his 19 NFL seasons, Smith played in 279 games, amassing a record 200 sacks, two interceptions, 46 forced fumbles, and 15 fumble recoveries, one of which he returned for a 33-yard touchdown. Of his 19 seasons in the NFL, 13 of them were seasons where he had at least ten sacks, a testament to his consistency year in and year out. He was also named to an All-Pro team ten times. As Smith spent most of his career in a 3–4 defensive scheme, a defensive scheme not geared toward creating sack opportunities for defensive ends, many consider the record particularly impressive. Indeed, Smith’s peers elected him to the Pro Bowl every season from 1987 to 1998 (with the exception of his injury-shortened 5-game 1991 season). In 1987, he was named the Pro Bowl MVP. Smith was twice named the AP’s NFL Defensive Player of the Year (1990, 1996), twice the NEA’s (1990, 1993) and four times the UPI’s AFC Defensive Player of the Year (1987, 1988, 1990, 1996).

Also in 1989, Bruce Smith signed an offer-sheet with the Denver Broncos for $7.5 million over five years, but the Bills matched the offer to retain him. In 1990, his defensive performance helped bring the Bills to Super Bowl XXV, though they eventually lost to the Bill Parcells-led New York Giants. Still, Smith had an impressive performance in the game. He sacked Jeff Hostetler in the end zone in the second quarter, becoming only the fifth player to record a Super Bowl safety. Later, Smith forced New York to turn the ball over on downs by tackling running back Ottis Anderson for a two-yard loss on a fourth down conversion attempt. Only a failed last-second field goal attempt kept the team from its first NFL championship (see Wide Right (Buffalo Bills)).

In 1991, though Smith’s knee problems forced him out for most of the season, the Bills once again reached the Super Bowl. In 1992, in much better health, he was again a First-team All-Pro and was voted to the Pro Bowl while recording a team-leading 14 sacks.

By 1996, though the Bills’ run of Super Bowl appearances had ended, Smith was still putting up prolific numbers, with 90 tackles and 14 sacks. In 1997, Smith had 65 tackles and 14 sacks and by 1998, although he was getting older he still had a respectable 50 tackles and ten sacks.

Smith had hinted in interviews that 2003 would be his final season, but never completely ruled out continuing to play. However, on February 24, 2004, the Redskins released Smith, saving $6.5 million in salary cap space.

Smith was arrested on May 15, 2009 and convicted on July 9, 2009 with driving under the influence, speeding, and refusing to take an alcohol breath test. Smith has two previous DUI arrests.