Pickens attended Murphy High School in Murphy, North Carolina, a small town in the foothills of the Smoky Mountains about 100 miles from Knoxville, Tennessee. He played free safety and wide receiver there, intercepting 15 passes in three seasons and catching 71 passes, including 24 for touchdowns, as a senior, when he was a Parade magazine All-American. He also returned punts and kickoffs, and punted. He also excelled at basketball, averaging 27 points per game and attracting the interest of many college programs.
Pickens played college football for the University of Tennessee from 1989–1991, where he started his career 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 Tennessee for his senior year. His college receiving statistics were:
Pickens was drafted in the second round (31st overall) of the 1992 NFL Draft by the Cincinnati Bengals.
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 nine NFL seasons, Pickens recorded 540 receptions for 7,129 yards and 63 touchdowns, while also gaining another 307 yards and one touchdown on punt returns. His 63 touchdown receptions were a franchise record until surpassed by Chad Johnson 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.
Pickens was arrested January 5, 2014 for allegedly assaulting his wife after the two argued on a movie date.