The previous day rumors circulated that Guyton had agreed to terms with the San Francisco 49ers, however confusion arose when 49ers General Manager Scot McCloughan said he would divulge names of undrafted free agents with whom the club had agreed to terms and the following day, Guyton had officially signed with the Patriots.

[1][2] Guyton, an undrafted free agent, made the Patriots' 53-man roster, and was active for all but one game of his rookie season in 2008, while the Patriots' third-round draft pick Shawn Crable, an outside linebacker, was inactive, and another inside linebacker, sixth-round draft pick Bo Ruud, was placed on injured reserve.

[3] In interviews, Patriots head coach Bill Belichick noted that they had debated drafting Guyton over Ruud, but ultimately chose Ruud;[4] in retrospect, Belichick admitted that the Patriots should have drafted Guyton and undrafted free agent running back BenJarvus Green-Ellis.

Guyton started at 4-3 middle linebacker for the Patriots in Weeks 2–5, in place of Mayo.

Following the season, the Patriots signed Guyton to a two-year extension worth over $2.1 million, including a $650,000 signing bonus; as Guyton was an exclusive rights free agent, the Patriots were only required to offer him a one-year minimum tender of $470,000.

[6] Guyton scored his first career touchdown in the Patriots' Week 1 game against the Cincinnati Bengals, on a 59-yard interception return of a Carson Palmer pass.

In 16 games played (eight starts), Guyton recorded 63 tackles, three sacks, two interceptions, and one forced fumble.