The Indianapolis Colts selected Bethea in the sixth round (207th overall) of the 2006 NFL Draft. Bethea was the 21st safety drafted in 2006.

On July 30, 2006, the Indianapolis Colts signed Bethea to a four-year, $1.67 million contract that includes a signing bonus of $79,420.

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. 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. On November 5, 2006, Bethea recorded nine combined tackles, two pass deflections, and intercepted a pass by Tom Brady during a 27–20 victory at the New England Patriots in Week 9. He was inactive during the Colts’ Week 13 loss at the Tennessee Titans due to an injury. The following week, he aggravated his shoulder injury and subsequently missed the Colts’ Week 15 victory against the Cincinnati Bengals. The Indianapolis Colts’ safeties sustained numerous injuries throughout the regular season, including strong safety Bob Sanders, who sustained a knee injury and was limited to four games. Veteran Mike Doss tore his ACL in Week 7 and missed the last nine games after being placed on injured reserve. Bethea started the first ten games and began developing a reputation for delivering big hits over the middle. His performance placed him in line as a possible rookie of the year candidate. He finished his rookie season with 90 combined tackles (66 solo), four pass deflections, and an interception in 14 games and 14 starts.

The Indianapolis Colts finished first in the AFC South with a 12–4 record. On January 6, 2007, Bethea started in his first career playoff game and recorded three solo tackles, a pass deflection, and intercepted a pass by quarterback Trent Green in the Colts’ 23–8 victory against the Kansas City Chiefs in the AFC Wildcard Game. The following week, he collected six combined tackles, broke up a pass, and intercepted a pass attempt by Steve McNair during a 15–6 win at the Baltimore Ravens in the AFC Divisional Round. The Indianapolis Colts went on to defeat the New England Patriots 38–34 in the AFC Championship to reach Super Bowl XLI. On February 4, 2007, Bethea started in Super Bowl XLI and made four combined tackles as they defeated the Chicago Bears 29–17.

On September 30, 2007, Bethea collected seven solo tackles during a 38–20 victory against the Denver Broncos in Week 4. The following week, he collected a season-high seven combined tackles, a pass deflection, and an interception in the Colts’ 33–14 victory against the Tampa Bay Buccaneers in Week 5. In Week 8, Bethea made a season-high three pass deflections, five combined tackles, and an interception during a 31–7 victory against the Carolina Panthers. Bethea missed the last three games of the regular season due to a knee injury (Weeks 15-17). He finished his second season with 65 combined tackles (43 solo), eight pass deflections, and four interceptions in 13 games and 13 starts. The Indianapolis Colts finished atop their division with a 12–4 record. 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. On January 28, 2008, it was reported that Bethea would be playing in the 2008 Pro Bowl. He was originally chosen as a second alternate and was needed after injuries to safeties Troy Polamalu and Bob Sanders.

Bethea and Sanders remained the starting safeties to begin the regular season. On November 2, 2008, Bethea recorded a season-high ten solo tackles during an 18–15 victory against the New England Patriots in Week 9. The following week, he collected a season-high 11 combined tackles (six solo) in the Colts’ 24–20 win at the Pittsburgh Steelers in Week 10. He finished the season with 101 combined tackles (74 solo), four pass deflections, and two interceptions in 16 games and 16 starts.

On January 12, 2009, head coach Tony Dungy retired ending Bethea’s three-year tenure under him. Assistant head coach Jim Caldwell retained Bethea as the starting strong safety, along with free safety Bob Sanders.

On September 21, 2009, Bethea collected a season-high eight solo tackles, a pass deflection, and an intercepted a pass by Tarvaris Jackson during a 27–23 victory at the Miami Dolphins in Week 2. In Week 7, he tied his season-high of eight solo tackles as the Colts’ routed the St. Louis Rams 42–6. On November 8, 2009, Bethea collected a season-high nine combined tackles (four solo) during a 20–17 win against the Houston Texans in Week 9. He finished the 2009 season with 95 combined tackles (70 solo), five pass deflections, and four interceptions in 16 games and 16 starts. On December 29, 2009, it was announced that Bethea was voted to the 2010 Pro Bowl, marking the second selection of his career.

The Indianapolis Colts finished first in the AFC South with a 14-2 record, clinching a first round bye and home-field advantage. On January 16, 2010, Bethea recorded three combined tackles, two pass deflections, and intercepted a pass by Joe Flacco during a 20–3 victory against the Baltimore Ravens in the AFC Divisional Round. The Colts went on to defeat the New York Jets 30–17 in the AFC Championship to reach Super Bowl XLIV. On February 7, 2010, Bethea started in Super Bowl XLIV and made four solo tackles during a 31–17 loss to the New Orleans Saints.

On March 3, 2010, the Indianapolis Colts placed a first round, $2.51 million tender on Bethea. He held out of organized team activities and declined to sign their restricted free agent tender. On July 11, 2010, the Indianapolis Colts signed Bethea to a four-year, $27 million contract that includes an $8 million signing bonus.

Defensive coordinator Larry Coyer retained Bethea and Sanders the starting safety duo to begin the 2010 regular season. 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. 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. The following week, he recorded a season-high 15 combined tackles (11 solo) during a 38–35 loss to the Dallas Cowboys in Week 13. 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.

Head coach Jim Caldwell named Bethea the starting free safety to begin the regular season, along with strong safety Melvin Bullitt. In Week 5, Bethea collected a season-high 12 combined tackles (six solo) in the Colts’ 28–24 loss to the Kansas City Chiefs. On November 6, 2011, Bethea recorded a season-high eight solo tackles and assisted on three more tackles during their 31–7 loss to the Atlanta Falcons in Week 9. He finished the 2011 season with a career-high 139 combined tackles (80 solo), seven pass deflections, two forced fumbles, and a fumble recovery in 16 games and 16 starts.

On January 3, 2012, Indianapolis Colts’ owner Jim Irsay fired general manager Chris Polian and vice chairman Bill Polian. 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.

Head coach Chuck Pagano retained Bethea as the Colts’ starting free safety to begin the regular season, along with strong safety Tom Zbikowski. 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. On November 8, 2012, he collected seven solo tackles and made his first career solo sack during a 27–10 victory at the Jacksonville Jaguars in Week 10. He sacked quarterback Blaine Gabbert for a one-yard loss in the fourth quarter. 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. He finished the 2012 season with 100 combined tackles (75 solo), seven passes defensed, and a career-high two sacks in 16 games and 16 starts.

Bethea entered training camp slated as the de facto starter at strong safety. Defensive coordinator Greg Manusky officially named Bethea the starting strong safety to start the regular season, opposite free safety LaRon Landry. Bethea started in the Indianapolis Colts’ season-opener against the Oakland Raiders and recorded 11 combined tackles (six solo), a pass deflection, and intercepted a pass by Terrelle Pryor in their 21–17 victory. This marked his first interception since 2010. On December 8, 2013, Bethea collected a career-high 17 combined tackles (ten solo) during a 42–28 loss at the Cincinnati Bengals in Week 14. 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.

On July 30, 2013, Bethea’s longtime college girlfriend, Samantha Romantini gave birth to a baby girl they named Siani. On June 28, 2014, Bethea married Romantini at the Ronald Reagan Building and International Trade Center in Washington D.C.

In December 2013, Bethea posed for PETA’s anti-fur campaign.

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.

On March 12, 2014, the San Francisco 49ers signed Bethea to a four-year, $21 million contract with $15.02 million guaranteed and a signing bonus of $5.25 million.

Head coach Jim Harbaugh named Bethea the starting strong safety to start the season, alongside free safety Eric Reid. He started in the San Francisco 49ers’ season-opener at the Dallas Cowboys and recorded six solo tackles and a pass deflection in their 28–17 victory. In Week 10, Bethea collected a season-high eight combined tackles, broke up a pass, and intercepted a pass by Drew Brees during a 27–24 overtime victory at the New Orleans Saints. 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. His touchdown occurred in the second quarter and marked the first score of his career. On December 24, 2014, it was announced that Bethea was selected to be an alternate for the 2015 Pro Bowl. 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. 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.

On January 19, 2015, Bethea was selected to replace Kam Chancellor in the 2015 Pro Bowl. Chancellor was unable to play due to this participation in the Super Bowl with the Seattle Seahawks.

Bethea and Eric Reid entered training camp slated as the starting safeties by defensive coordinator Vic Fangio. 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. On October 22, 2015, Bethea made five combined tackles before exiting a 20-3 loss to the Seattle Seahawks in the third quarter with an injury. The following day, the San Francisco 49ers placed him on injured reserve with a torn pectoral muscle. Bethea finished the 2015 season with a total of 44 combined tackles (32 solo), two passes defensed, and an interception in seven games and seven starts.

On January 4, 2016, the San Francisco 49ers fired head coach Jim Tomsula after they finished 2015 with a 5–11 record. The San Francisco 49ers hired former Philadelphia Eagles’ head coach Chip Kelly as their head coach for the 2016 season. This became Bethea’s fourth different coach in the last four seasons. Head coach Chip Kelly retained Bethea and Eric Reid as the starting safety tandem to start the regular season. On September 18, 2016, Bethea recorded nine combined tackles, a pass deflection, and intercepted a pass by quarterback Cam Newton in a 45–27 loss at the Carolina Panthers in Week 2. In Week 4, he collected a season-high 12 combined tackles (11 solo) and broke up a pass during a 24–17 loss to the Baltimore Ravens. Bethea started all 16 games in 2016 recording 110 combined tackles (96 solo), three passes defensed, one forced fumble, and an interception in 16 games and 16 starts. Pro Football Focus gave Bethea an overall grade of 72.5 and ranked 66th among the 88 qualifying safeties in 2016.

On January 1, 2017, the San Francisco 49ers announced the firing of head coach Chip Kelly after the team finished with a 2-14 record. On March 7, 2017, the San Francisco 49ers released Bethea, granting his request to be released.

On March 9, 2017, the Arizona Cardinals signed Bethea to a three-year, $12.75 million contract that includes $4 million guaranteed and a signing bonus of $2 million.

On October 15, 2017, Bethea recorded five combined tackles, a pass deflection, and intercepted a pass by quarterback Jameis Winston during a 38–33 victory against the Tampa Bay Buccaneers in Week 6. The interception marked his third consecutive game with a pick. The following week, he collected a season-high 11 combined tackles (ten solo) and a pass deflection in the Cardinals’ 33–0 loss at the Los Angeles Rams in Week 7. 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. Bethea remained the backup strong safety behind Baker for the remainder of the season. On December 24, 2017, Bethea made three solo tackles, two pass deflections, and intercepted two pass attempts by Eli Manning in a 23–0 win against the New York Giants in Week 16. On December 26, 2017, the Arizona Cardinals placed Bethea on injured reserve after he tore his pectoral a muscle in Week 16. He completed the 2017 season with 57 combined tackles (47 solo), nine pass deflections, a career-high five interceptions, and a sack in 15 games and six starts. Pro Football Focus gave Bethea an overall grade of 86.7, which was the 13th highest grade among all qualifying safeties in 2017.

On January 2, 2018, head coach Bruce Arians announced his retirement and resigned as head coach of the Cardinals. The Arizona Cardinals hired Steve Wilks who became Bethea’s sixth head coach in as many seasons. He was named the Cardinals starting free safety, starting in all 16 games. He finished the season with a team-leading 120 tackles, four pass deflections, and a career-high three sacks.

On March 8, 2019, Bethea was released by the Cardinals.

On March 14, 2019, Bethea signed with the New York Giants. 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. 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.

On March 18, 2020, the Giants informed Bethea that they would not exercise his contract option, making him a free agent.