O'Donnell was drafted by the Steelers with the 70th overall pick in the 1990 NFL draft. After sitting on the bench for his entire rookie season, he started in eight games during 1991 before becoming the team's full-time QB in 1992. O'Donnell led the Steelers to Super Bowl XXX, but threw two interceptions to Dallas CowboyscornerbackLarry Brown to set up short touchdown drives in the second half.
Following the Super Bowl letdown, O'Donnell became a free agent, and although the Steelers made an offer, he signed with the New York Jets, where he was 0–6 in his first season as starter before suffering a season-ending shoulder injury despite throwing for 292 or more yards in three of these starts. His performance would improve the following season under new coach Bill Parcells the following year, 1997.
In 1998, with the then-1–3 Bengals, O'Donnell threw a 25-yard touchdown pass to Carl Pickens with 20 seconds remaining to score the winning touchdown against 3–1 Pittsburgh. O'Donnell's 90.2 passer rating was sixth among regular starting quarterbacks in the NFL and third in the AFC. However, due to a poor defense, the Bengals would go on to finish 3–13. O'Donnell was released at the end of the season to make room for rookie quarterback Akili Smith.
From 1999 onwards, O'Donnell was Steve McNair's backup with the Titans. He performed well, winning four of his five starts for an injured McNair in 1999, leaving a perennial .500 team at 5-1 upon McNair's return. Later, O'Donnell came off the bench and led Tennessee to a Week 17 47-36 victory in Pittsburgh en route to the AFC Championship and Super Bowl XXXIV, which he was not an active participant in.
O'Donnell retired after the 2002 season, but was talked into coming back for one game in December 2003 when McNair and Billy Volek were injured. He started in the regular-season finale and delivered a fine performance, completing 18 of 27 passes for 232 yards and two touchdowns, leading the Titans to a 33-13 victory over the Tampa Bay Buccaneers.
O'Donnell ended his career with the lowest interception percentage in NFL history, averaging just 2.11 interceptions for every 100 pass attempts, although this statistic is somewhat diminished by the costly ones he threw in the Super Bowl.Aaron Rodgers has since eclipsed the record (1.99 interception percentage through the 2010-11 season). O'Donnell also wore number 14 during most of his career except during his one-year stint with the Bengals, where he wore number 12. The Bengals haven't issued number 14 since the retirement of former quarterback & West Coast offense pioneer Ken Anderson--coincidentally, now the quarterbacks coach for the Steelers.Andy Dalton now wears number 14 for the Bengals.