Mayo was considered one of the best linebackers available in the 2008 NFL Draft and drew comparisons to Will Witherspoon. Sporting News described Mayo as a “perfect fit to play one of the inside spots” in a 3-4 defense.
The New England Patriots selected Mayo in the first round (10th overall) of the 2008 NFL Draft. Mayo was the second linebacker drafted in 2008, behind Keith Rivers.
On July 24, 2008, the New England Patriots signed Mayo to a five-year contract (rather than the six-year maximum allowed by the NFL's collective bargaining agreement) worth $18.9 million, including $13.8 million in bonuses and guarantees. Mayo was the only rookie in the Patriots' 2008 class to start in Week 1, and played every snap for the defense.
Mayo was named the NFL's Defensive Rookie of the Month for October 2008. He led the Patriots with 24 tackles for the month, including 11 against the Denver Broncos in his first Monday Night Football appearance. In the Patriots' Thursday Night Football game on November 13, 2008, against their division rivals, the New York Jets, Mayo led all defensive players with 20 tackles (16 solo, 4 assisted), the first 20-tackle game of his career.
Mayo has two brothers, both of whom played college football as linebackers. His younger brother, Deron Mayo, played in the Canadian Football League, and is currently the assistant strength and conditioning coach for the New England Patriots. His brother Derek Mayo is a graduate of Richmond, where he won the NCAA Football Championship Subdivision title in 2008.