After his High school career, Pickens played college football for the University of Tennessee from 1989–1991, where he started his career off as a Safety and was named a Freshmen All-American and All-SEC selection. He then moved to wide receiver where he caught 109 passes for 1,875 yards and 13 touchdowns, and made the College Football All-America Team as a junior. He did not return to the University of Tennessee for his senior year.
1989: 7 catches for 81 yards with 2 TD.
1990: 53 catches for 917 yards with 6 TD.
1991: 49 catches for 877 yards with 5 TD.
In 1992 Pickens was named The NFL Offensive Rookie of the Year by the Associated Press. In 1995, he set a Bengals record for receptions in a single season with 99, and touchdown catches with 17. Pickens later surpassed his own record by recording 100 receptions in 1996. In his 9 NFL seasons, Pickens recorded 540 receptions for 7,129 yards and 63 touchdowns, while also gaining another 307 yards and 1 touchdown on punt returns. His 63 touchdown receptions were a franchise record until surpassed by Chad Ochocinco in 2010.
He is also known for the "Carl Pickens Clause". This was a loyalty clause that the Bengals created and added to Pickens' contract which would cause him to forfeit all or some of his signing bonus if he insulted the organization in public. This clause has since been used in contracts with other players.