He played college football for the Virginia Tech Hokies, where he was a twice All-American, and was selected with the first overall pick by the Bills in the 1985 NFL draft.

Considered one of the greatest defensive ends of all time, Smith is the NFL's all-time career leader in quarterback sacks with 200.

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.

In March 1989, as a restricted free agent, Smith signed an offer-sheet with the Denver Broncos for $7.5 million over five years.

Smith had excelled as their defensive leader, but the Bills were concerned about him with his substance abuse problem (since he had been suspended four games the previous year for it) and thus had him followed by undercover detectives in November, which stuck with him months later.

He responded by playing in all sixteen games of the season and recording thirteen sacks to make his third straight Pro Bowl.

[5] He recorded half a sack in the divisional round playoff game that year, which the Bills lost to the Cleveland Browns 34–30.

He did not have a sack in either of the first two playoff games for the Bills, but Smith saved his efforts for Super Bowl XXV against the New York Giants.

[7] 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.

By 1996, though the Bills' run of Super Bowl appearances had ended, Smith was still putting up prolific numbers, with ninety tackles and fourteen sacks.

[13][14] Smith, along with Andre Reed and Thurman Thomas, was dumped from the Bills roster in an emergency salary cap measure after the 1999 season.

Having returned to his home state, Smith works as a large-scale hotel designer, undertaking many projects with Armada Hoffler.