The Philadelphia Eagles selected him in the first round (sixth pick overall) of the 2000 NFL Draft, and he played for the Eagles from 2000 until 2005. He started in four NFC Championship games during his six seasons with the Eagles. Philadelphia reached the Super Bowl once during these years, losing Super Bowl XXXIX to the New England Patriots, 24-21. After the 2004 season, the Eagles placed the franchise tag on Simon, which he refused to sign. After contract negotiations failed to produce a long-term deal, the Eagles lifted the franchise tag, making Simon an unrestricted free agent.
Simon signed with the Indianapolis Colts, for whom he played the entire 2005 season. In 2006, Simon underwent surgery, was placed on the Physically Unable to Perform / Non-Football Injury list during training camp, and did not play in any games. He did not attend Super Bowl XLI with other inactive players, and was not invited to the Super Bowl ring ceremony in June 2007. He was once coined "the missing piece to the Super Bowl puzzle".
On August 1, 2007, Colts owner Jim Irsay stated that Simon's release from the team was imminent once a settlement could be reached. The team announced Simon's termination on Saturday, August 4, 2007.