Spikes entered the 1998 NFL draft and was selected in the first round by the Cincinnati Bengals.

He wrote his dad's name on the tape he wrapped around his wrists for the remaining 12 games of the season.

He led the team in solo and total tackles once again and scored his second defensive TD by way of fumble recovery.

Following the season, Spikes was given the designated player tag making him a restricted free agent.

(However, the Bills did not make the playoffs for the entire 2000s decade, while the Bengals went 11–5 and won their division in 2005).

The Buffalo Bills signed Spikes to an offersheet worth $32 million over six years, that the Bengals did not match.

On September 25, 2005, Spikes suffered a season-ending tear to his right Achilles' tendon while tackling Michael Vick during the Bills' 24–16 loss to the Atlanta Falcons in Week 3.

During the first series of the first game of the year, Spikes made a blind side sack on Patriots QB Tom Brady, forcing a fumble which was recovered by Bills LB London Fletcher for a touchdown.

On March 26, 2007, he was traded alongside Kelly Holcomb to the Philadelphia Eagles, in exchange for Darwin Walker and a 2008 NFL draft selection.

With emerging linebackers Stewart Bradley and Omar Gaither ready to take over, the Eagles chose not to pick up his team option, thus making him a free agent.

On August 10, 2008, Spikes was signed by the San Francisco 49ers on the same day they released linebacker Brandon Moore.

On September 11, 2012, Spikes played his 200th career start earning him membership in a very elite group of linebackers to reach this achievement.

On September 30, 2012, he forced Jamaal Charles to fumble when playing against the Kansas City Chiefs.

[21] Takeo's younger cousin Brandon Spikes is a former linebacker who played for the New England Patriots and the Buffalo Bills.

He was featured in ESPN The Magazine's "The Body Issue" in 2012 with a focus on his neck and trapezius.

[26] Spikes provides mentoring at his annual TKO camp where he inspires young boys and girls to reach their goals.

The mission of the camp is to help the participants bridge the gap of taking their goals from dreams to reality.

The annual event also includes a financial contribution to the local Washington County, GA athletic department.