Lewis played at Hialeah Miami Lakes High School under coach Jerry Hughes. As a senior, he was evaluated as the nation's 10th-best dual-threat quarterback and 65th-best quarterback overall. He led his team to the state playoffs that year, passing for 12 touchdowns and only three interceptions.
Lewis played college football for the Duke Blue Devils. While at Duke he set school records for career passing touchdowns and career passing yards. He also set Duke's school record for most consecutive pass attempts without an interception, 206. During his four years as a starting quarterback, he threw for 10,065 yards, 67 touchdowns and 40 interceptions, and ran for 9 touchdowns.
During his senior season Lewis was a finalist for the Davey O'Brien Award, presented to the nation's top quarterback.
The Cleveland Browns claimed him off of waivers on September 4, 2011. Lewis was later waived by the Browns on October 11, 2012. He was signed to the practice squad on October 13, 2012. He was again added to the Cleveland Browns active roster December 24, 2012 after injuries to Brandon Weeden and Colt McCoy. He made his first career start when the Browns took on the Pittsburgh Steelers on December 30, 2012 and completed 22 of 32 passes for 204 yards with one touchdown and one interception. Notwithstanding Lewis' performance, the Browns lost 24-10. This performance was particularly noteworthy due to his strong performance against the first ranked defense of the NFL during the 2012 season.
On August 25, 2013, the Buffalo Bills traded linebacker Chris White for Lewis, due to the mounting quarterback injuries for the Bills. He was released on August 31, 2013 and signed to the practice squad September 1. On October 7, 2013, coach Doug Marrone announced on WGR Radio 550 that Lewis was promoted to the active roster from the practice squad after an injury to EJ Manuel and started week 6 against the Cincinnati Bengals, over undrafted rookie Jeff Tuel, where he went 19/32 for 216 yards with 2 passing touchdowns and 0 interceptions and added 7 carries for 17 yards and 1 rushing touchdown. The Bills lost the game in overtime by a score of 27-24. A week later on October 20, 2013, Lewis went 21/32 for 202 yards with 0 touchdown passes and 1 interception. He also had 5 carries for 13 yards as he earned his first career victory against the Miami Dolphins by a score of 23-21. In a week 8 loss to the New Orleans Saints, Lewis completed 22 of 39 passes for 234 yards, 1 touchdown and 1 interception along with 2 rushes for 5 yards. This game is arguably his worst as he fumbled the ball 3 times. On November 3, 2013 against the Kansas City Chiefs in week 9, Jeff Tuel was named the starting quarterback, only to be replaced the following week by the original week 1 starter, E.J. Manuel. Manuel started the next 5 games against the Pittsburgh Steelers, New York Jets, Atlanta Falcons, Tampa Bay Buccaneers, and Jacksonville Jaguars. Lewis received his second win as a member of the Bills during week 16 in a shut out victory over their division rival, the Miami Dolphins, with a score of 19-0. He went 15/25 for 193 yards with zero touchdowns and 1 interception while adding 8 carries for 13 yards. This loss would be a major factor for the Dolphins not making the playoffs since they needed to win just one of their final two games for a wildcard spot; which they lost both. In his final game as a Bill, Lewis played at Foxborough Stadium against Tom Brady and the New England Patriots. Although Lewis outshined Brady on that day, by throwing for more yards than him and not throwing an interception like Brady did, his team lost to the Patriots by a score of 34-20. Lewis went 16/29 for 247 yards with 1 touchdown and no interceptions. He also added 2 carries for 4 yards. Thad Lewis finished his 2013 Bills season with a 2-3 record as Buffalo's starting quarterback. On August 26, 2014, Lewis was released from the Bills.
Lewis signed with the Houston Texans on November 24, 2014, after starting quarterback Ryan Mallett suffered an season ending injury, but was then released during the off season leading up to the 2015 season.