In the 1996 NFL draft, Simeon Rice was selected third overall by the Arizona Cardinals. He was selected after Keyshawn Johnson and Kevin Hardy. After a contract dispute that lasted through training camp, Rice signed a 4-year, $9.5 million deal. Lining up at defensive end, Rice’s first snap as a pro resulted in a tackle for a 2-yard loss on Indianapolis Colts running back Marshall Faulk. At the end of September, Rice had 5 sacks and was named NFL defensive rookie of the month. At the end of the season, Rice had 12.5 sacks which tied a rookie record and he was voted NFL Defensive Rookie of the Year by the Associated Press. In Rice’s second season with the Cardinals, they finished 4-12. The fans grew impatient with the team. Rice himself lost the admiration of the fans by playing semi-professional basketball for the Philadelphia Power of the USBL. He played 11 minutes a game averaging 2.5 points and was paid $400 a game. In Rice’s third season, the Cardinals made the playoffs and won their first post-season game since 1947. That season Rice had 10 sacks, 23 quarterback pressures, and 4 fumble recoveries. The following year, the team slipped to 6-10 in part because of injuries to many of their star players. Despite the team’s poor play, Rice had 16.5 sacks and was named to his first Pro-Bowl. The next season, the year 2000, Rice was due a big pay increase, but the contract negotiation kept him off the field until the second game of the regular season. Rice had 7.5 sacks and the Cardinals fell to 3-13. At the end of the season, Rice was a free agent and was anxious to go to a new team.

After sitting out the 2008 season, Rice signed with the New York Sentinels of the United Football League on August 27, 2009.

Rice’s first feature-length film as director, Unsullied, was released on August 28, 2015. The film stars Murray Gray, Rusty Joiner and James Gaudioso.