Alongside Cornelius Bennett and later Keith McCants at Alabama, Thomas spearheaded one of the best defensive lines in college football and smashed many Crimson Tide defensive records, including sacks in a single season. He was awarded the Butkus Award in 1988 after a season which saw him set an NCAA record 27 sacks along with finishing 10th in Heisman Trophy balloting. He currently holds the single season NCAA FBS sack record with 27 and what was the career sack record with 52 career sacks. He was also selected as a unanimous All-American at the conclusion of the 1988 season, a season which culminated in the Crimson Tide’s thrilling 29-28 victory over Army in the 1988 Sun Bowl. In 2000, Thomas was named a Sun Bowl Legend. He was awarded the Sington Soaring Spirit Award by the Lakeshore Foundation. This annual award is named for University of Alabama football legend Fred Sington. Thomas was elected to the College Football Hall of Fame in 2014.

Thomas was known for his ability to sack the quarterback and was named a First Team All-Pro two times, Second Team All-Pro four times, and was voted to nine Pro Bowls in his 11-year career. He totaled 126.5 sacks in his career, and as of the start of the 2017 NFL season, holds the single game record of seven quarterback sacks, a feat which occurred against Seattle’s Dave Krieg on 1990 Veterans Day. Despite this feat, Krieg eluded a blitzing Thomas on the game’s last play and threw a touchdown pass to Paul Skansi, which gave the Seahawks a 17–16 win. The record came close to being matched with three occasions of players reaching six sacks, once by Thomas himself in 1998.

In 1990, Thomas founded the Derrick Thomas Third and Long Foundation. The foundation’s mission is to “sack illiteracy” and change the lives of 9- to 13-year-old urban children facing challenging and life-threatening situations in the Kansas City area.

On January 23, 2000, Thomas’ 1999 Chevrolet Suburban went off Interstate 435 in Clay County as he and two passengers were driving to Kansas City International Airport during a snowstorm for a flight to St. Louis to watch the NFC Championship Game between the St. Louis Rams and the Tampa Bay Buccaneers. Police reports indicated that Thomas, who was driving, was speeding at approximately 70 m.p.h. even though snow and ice were rapidly accumulating on the roadway. Thomas and one of the passengers were not wearing seat belts and both were thrown from the car; the passenger, Michael Tellis, was killed instantly. The second passenger, who was wearing his safety belt, walked away from the scene uninjured. Thomas was left paralyzed from the chest down. By early February, Thomas was being treated at Miami’s Jackson Memorial Hospital. The morning of February 8, 2000, while being transferred from his hospital bed to a wheelchair on his way to therapy, Thomas told his mother he was not feeling well. His eyes then rolled back, recalled Frank Eismont, an orthopedic surgeon at Jackson Memorial Hospital. Eismont said Thomas went into cardiorespiratory arrest and died as a result of a pulmonary embolism, a massive blood clot that developed in his legs and traveled to his lungs. Months later, Thomas’ family sued General Motors for $73 million in damages stemming from the accident. In 2004, a jury ruled that the family was not entitled to any money.

The Derrick Thomas Academy, a charter school in Kansas City, Missouri, opened in September 2001. It served nearly 1,000 children from kindergarten through eighth grade until it closed in 2013.

On January 31, 2009, Thomas was posthumously named among six players selected for induction into the Pro Football Hall of Fame, his fifth year of eligibility. He was officially posthumously inducted in Canton, Ohio on August 8, 2009, after four years as a finalist in the Hall of Fame voting. The Chiefs announced on June 23, 2009, that they would retire #58 in honor of Thomas, and the retirement ceremony took place on December 6, 2009, when the Chiefs played the Denver Broncos.