The Bills also said they reached terms with former San Francisco running back Anthony Dixon.
Spikes had 86 tackles and an interception last season for New England, the former Florida player's fourth with the Patriots.
''Gotta silence the lambs, get on my Buffalo Bill! (hashtag)51 (hashtag)BILLSMAFIA taking back the (hashtag)AFCEAST (hashtag)PoWwWwW,'' Spikes tweeted.
He's rejoining former Patriots linebackers coach Pepper Johnson, the Bills' new defensive line coach.
Dixon ran for 458 yards and eight touchdowns in four seasons San Francisco, but dropped down the depth chart behind Frank Gore and Kendall Hunter. Dixon played some at fullback after Bruce Miller was injured.
Bills general manager Doug Whaley has been busy, also adding linebacker Keith Rivers, guard Chris Williams and cornerback Corey Graham and re-signing tight end Scott Chandler.
Spikes is regarded as a key addition for a defense that struggled against the run last season and is under transition with Jim Schwartz taking over as coordinator. Schwartz replaces Mike Pettine, who left Buffalo after one season to take over as Cleveland's head coach.
The deal with Spikes will allow the Bills to move Kiko Alonso to an outside role, a position they believe he's best suited.
Buffalo allowed 150 or more yards on the ground seven times last season. That was a glaring weakness of a defense that otherwise was solid in other areas in setting a franchise-record 57 sacks and finishing 10th in the NFL in yards allowed, Buffalo's best finish since ranking second in 2004.
AP freelance writer Nick Mendola contributed to this report.
AP NFL website: www.pro32.ap.org and http://twitter.com/AP-NFL