He played college football for the Howard Bison and was selected by the Indianapolis Colts in the sixth round of the 2006 NFL draft.

Bethea would continue his success in his senior season, collecting 88 tackles, six passes defensed and a career-high four interceptions in 10 games.

[12] He made his professional regular season debut and first career start in the Indianapolis Colts' season-opener at the New York Giants and recorded six combined tackles and a pass deflection in their 26–21 victory.

[13] In Week 3, he collected a season-high 12 combined tackles (eight solo) and broke up a pass in the Colts' 21–14 win against the Jacksonville Jaguars.

[13] On February 4, 2007, Bethea started in Super Bowl XLI and made four combined tackles as they defeated the Chicago Bears 29–17.

Defensive coordinator Ron Meeks retained Bethea and Bob Sanders as the starting safeties to begin the regular season.

On January 13, 2008, Bethea started in the AFC Divisional Round and recorded seven combined tackles during a 28–24 loss to the San Diego Chargers.

[10][30] Defensive coordinator Larry Coyer retained Bethea and Sanders the starting safety duo to begin the 2010 regular season.

[31] Bethea started in the Indianapolis Colts season-opener at the Houston Texans and collected a 13 combined tackles (eight solo) and a pass deflection in their 34–24 loss.

[32] On November 28, 2010, Bethea made six combined tackles and was credited with half a sack on Philip Rivers in the Colts' 36–14 loss to the San Diego Chargers in Week 12.

[32] He finished with 107 combined tackles (77 solo), five pass deflections, an interception, a forced fumble, and half a sack in 16 games and 16 starts.

[35] On January 17, 2012, new general manager Ryan Grigson decided to fire head coach Jim Caldwell after the Colts finished with a 2–14 record.

[37] He started in the Indianapolis Colts' season-opener at the Chicago Bears and recorded a season-high nine solo tackles and two pass deflections in their 41–21 loss.

[38] On December 16, 2012, Bethea made five solo tackles and sacked quarterback Matt Schaub in the Colts' 29–17 loss at the Houston Texans in Week 15.

Bethea finished his last season with the Indianapolis Colts with a total of 110 combined tackles (80 solo), six pass deflections, an interception, and a sack in 16 games and 16 starts.

[19] Bethea became an unrestricted free agent in 2014 and drew interest from multiple teams, including the Detroit Lions, San Francisco 49ers, Philadelphia Eagles, Green Bay Packers, and Kansas City Chiefs.

[48] On December 20, 2014, Bethea recorded a season-high tying eight combined tackles, two pass deflections, and returned an interception by Philip Rivers for a 49-yard touchdown during a 38–35 overtime loss to the San Diego Chargers in Week 16.

[50] On December 28, 2014, it was announced that the San Francisco 49ers and head coach Jim Harbaugh decided to mutually part ways after the 2014 season.

[51] He finished his first season in San Francisco with 86 combined tackles (72 solo), ten pass deflections, four interceptions, a forced fumble, and a touchdown in 16 games and 16 starts.

[52] Bethea and Eric Reid entered training camp slated as the starting safeties by defensive coordinator Vic Fangio.

[53] The San Francisco 49ers' new head coach Jim Tomsula officially named Bethea and Reid the starters entering the regular season.

In Week 5, Bethea collected a season-high ten combined tackles (six solo) and a pass deflection during a 30–27 loss at the New York Giants.

[63] Head coach Bruce Arians named him the backup free safety behind Tyvon Branch to start the regular season.

[66] He was surpassed on the depth chart by rookie first round pick Budda Baker after Tyvon Branch was placed on injured reserve for the remainder of the season.

[74] In week 8 against the Detroit Lions, Bethea forced a fumble on wide receiver Kenny Golladay and recovered the football in the 31–26 loss.

[75] In week 9 on Monday night football against the Dallas Cowboys, Bethea intercepted a pass from Dak Prescott on the first play of the game and recovered a fumble forced by teammate Jabrill Peppers on Randall Cobb in the 37–18 loss.

[78] On July 30, 2013, Bethea's longtime college girlfriend, Samantha Romantini gave birth to a baby girl they named Siani.

[79] On June 28, 2014, Bethea married Romantini at the Ronald Reagan Building and International Trade Center in Washington D.C.[80] The pair have since had two sons, born in 2016 and 2019.

He attended Denbigh High School in Newport News, Virginia[81] where he was a three-year letterman in football and also lettered in basketball, where he earned all-area and All-conference honors in his senior year.