Mayo played college football for the Tennessee Volunteers, receiving first-team All-SEC honors, and was selected by the Patriots 10th overall in the 2008 NFL draft.

During his playing career, Mayo was named Defensive Rookie of the Year, earned first-team All-Pro honors in 2010 after leading the league in tackles, and received two Pro Bowl selections.

He attended Kecoughtan High School in Hampton, where he earned three letters in football as a linebacker and a running back.

Also playing running back for seven games, he picked up 1,245 rushing yards and scored 13 touchdowns and five two-point conversions during his final campaign.

As a junior, he recorded 68 tackles including 22 for loss, four interceptions and three sacks and earned first-team All-District, All-Area and All-Region honors.

[4] Jerod's younger brother, Deron Mayo, was a linebacker for the Calgary Stampeders of the Canadian Football League.

Mayo was a first-team All-Southeastern Conference selection and also earned All-American second-team honors by The NFL Draft Report.

[13] He led the Patriots with 24 tackles for the month, including 11 against the Denver Broncos in his first Monday Night Football appearance.

In Week 12, Mayo's eight tackles gave him 132 on the season, surpassing his previous career high of 128, set in 2008.

[30] On October 16, Mayo was placed on injured reserve with a torn patellar tendon that he suffered in a game against the Buffalo Bills in Week 6.

[31] Without Mayo, the Patriots won Super Bowl XLIX after they defeated the defending champion Seattle Seahawks by a score of 28–24.

[32] Mayo's playing time dipped in the 2015 season, being behind Dont'a Hightower and Jamie Collins on the depth chart.

[33] On January 19, 2016, days before the AFC Championship against the Denver Broncos, Mayo was placed on injured reserve with a shoulder injury.

[34] On February 16, 2016, Mayo posted a message on his Instagram account announcing his retirement, thanking the Patriots for the previous eight years.

[38] Mayo also became the youngest head coach in the NFL until a few weeks later when the Seattle Seahawks hired Mike Macdonald.

Two of his brothers were also linebackers: his younger brother, Deron Mayo, played in the Canadian Football League and is currently the head strength and conditioning coach for the New England Patriots,[48][49] and Derek Mayo is a graduate of Richmond, where he won the NCAA Football Championship Subdivision title in 2008.