Thomas grew up playing football on the Missouri City Junior High School (now Missouri City Middle School) and Willowridge High School teams before attending college at Oklahoma State University. At Oklahoma State, Thomas had 897 rushes for 4,595 yards, 43 touchdowns, and 21 100-yard rushing games. He was also a Heisman Trophy candidate in his senior year. He was a first team selection on the College Football All-America Team in 1985 and 1987.

A knee injury damaged Thomas's certain first round pick status and caused him to slip into second round (40th overall) of the 1988 NFL draft by the Buffalo Bills, their first choice in the draft. Thomas is well known as part of the offense that included Jim Kelly and Andre Reed, which led the Bills to four straight Super Bowl appearances.

Thomas was the AFC rushing leader in 1990, 1991, and 1993. He was voted to the All-Pro team in 1990 and 1991, was selected to 5 straight Pro Bowls from 1989-1993, and was named NFL Offensive Player of the Year in 1991.

Thomas currently holds the all-time Buffalo Bills rushing record with 11,938 yards and the team record for yards from scrimmage with 16,532. He is also 4th overall in team scoring. Overall, Thomas finished his 13 seasons with 12,740 rushing yards, 472 receptions for 4,458 yards, and 88 touchdowns(65 rushing and 23 receiving).

Thomas is the only player in NFL history to lead the league in total yards from scrimmage for four consecutive seasons. He is one of only four running backs to have over 400 receptions and 10,000 yards rushing. Walter Payton, Marshall Faulk and Marcus Allen are the other three. Thomas is also one of four running backs to have rushed for over 1,000 yards in 8 consecutive seasons along with Curtis Martin, Barry Sanders and Emmitt Smith.

Thomas also set NFL playoff records with the most career points (126), touchdowns (21), and consecutive playoff games with a touchdown (9). Overall, he rushed for 1,442 yards and caught 76 passes for 672 yards in his 21 postseason games. In a 1989 playoff loss to the Cleveland Browns, Thomas recorded 13 receptions for 150 yards and 2 touchdowns, which was a postseason record for receptions by a running back and tied tight ned Kellen Winslow's record for most receptions in a playoff game. He is also the first player ever to score a touchdown in 4 different Super Bowls

Thurman Thomas played for the Buffalo Bills for 12 seasons. When the Bills ran out of money under their salary cap in 2000, Thomas signed with the arch-rival Miami Dolphins. He suffered a knee injury on November 12, 2000 against the San Diego Chargers which ended his NFL career. After deciding to retire, Thurman signed a one-day contract on February 27, 2001 with Buffalo so that he could retire as a Bill.

Thurman Thomas was first eligible for induction into the Pro Football Hall of Fame in 2006. In that year, he made it to the list of ten finalists, but was not one of the six players elected to the Hall that year.