He played college football for the Tennessee Volunteers and was selected by the Denver Broncos in the first round of the 2009 NFL draft.

[11] The Broncos drafted Ayers with the first round pick that was traded from the Chicago Bears in exchange for Jay Cutler.

[14] Ayers's second season was a bit of a disappointment to fans who were hoping for high production from the former first-round draft selection.

[15] Ayers finished the 2011 season with three sacks, 39 total tackles, three passes defended, and one forced fumble.

[26][27] On March 12, 2016, Ayers agreed to a three-year, $21 million contract with the Tampa Bay Buccaneers.

[28] On September 11, Ayers recorded a sack in his Buccaneers debut, bringing down Matt Ryan in a 31–24 win over the Atlanta Falcons.

[30][31] On November 13, he recorded a season-high 1.5 sacks and five tackles, as well as forcing fumble in the end zone, resulting as a safety in a 36–10 blowout win over the Chicago Bears.

[33] On October 22, 2017, Ayers brought down his first sack of the season, dropping Tyrod Taylor in a 27–30 loss to the Buffalo Bills.

[43] Key Ayers joined the University of Tennessee coaching staff as a defensive graduate assistant before the 2023 season.