The New Orleans Saints selected Jenkins in the first round (14th overall) of the 2009 NFL Draft. Jenkins was the first cornerback to be drafted by the Saints in the first round since Oregon’s Alex Molden went eleventh overall in the 1996 NFL Draft.

Considered a three-star recruit by Rivals.com, Jenkins was listed as No. 61 cornerback prospect in the nation in 2005.

During his freshman season at Ohio State, Jenkins spent most of his time in the nickelback position. He finished the season with 37 tackles in 10 games. In 2006, he started all 13 games at corner and was a consensus first-team All-Big Ten. He finished ’06 with 55 tackles and four interceptions. As a junior in 2007 Jenkins recorded 47 tackles and four interceptions and was named a first team All-American by Pro Football Weekly and a first team All-Big Ten for the second consecutive year. As a senior in 2008 he won the Jim Thorpe Award, which is given to the nation’s best defensive back, after recording 57 tackles and three interceptions.

On August 9, 2009, the New Orleans Saints signed Jenkins on a five-year, $19 million contract that includes $10.59 million guaranteed. Their agreement ended Jenkins’ 11-day training camp holdout.

He made his professional regular season debut in the New Orleans Saints’ season-opener against the Detroit Lions and made one solo tackle in their 45–27 victory. He made first career tackle on running back Aaron Brown and stopped him from scoring on an 87-yard kick return in the third quarter. He was inactive for the Saints’ Week 4 victory against the New York Jets after spraining his ankle the previous week. Jenkins was sidelined for Week 6 after further aggravating his ankle injury. On November 22, 2009, Jenkins earned his first career start and recorded seven combined tackles, two pass deflections, and intercepted his first career pass during a 38–7 victory at the Tampa Bay Buccaneers in Week 11. Jenkins intercepted a pass attempt by quarterback Josh Freeman that was originally intended for wide receiver Antonio Bryant and returned it for a 14-yard gain in the second quarter. He earned his first start after Jabari Greer sustained a groin injury in Week 9 and Tracy Porter sprained his MCL in Week 10. Jenkins remained the starter for the next six games after Greer was sidelined for the next seven games (Weeks 10–16) and Porter was sidelined for the next four games (11–14) In Week 13, he collected a season-high nine solo tackles and broke up a pass in a 33–30 win at the Washington Redskins. On December 27, 2009, Jenkins made a season-high ten combined tackles (eight solo) in the Saints’ 20–17 loss to the Tampa Bay Buccaneers in Week 16. Jenkins finished his rookie season in 2009 with 55 combined tackles (49 solo), four pass deflections, and an interception in 14 games and six starts.

The New Orleans Saints finished first in the NFC South with a 13–3 record, clinching a first round bye and home-field advantage throughout the playoffs. On January 16, 2010, Jenkins appeared in his first career playoff game as the Saints’ defeated the Arizona Cardinals 45–14 in the NFC Divisional Round. The Saints reached the Super Bowl after winning the NFC Championship Game in a 31–28 win against the Minnesota Vikings. On February 7, 2010, Jenkins appeared in Super Bowl XLIV and recorded five solo tackles and a pass deflection in the Saints’ 31–17 victory against the Indianapolis Colts.

On May 8, 2010, head coach Sean Payton stated his intentions to move Jenkins to safety while addressing the media at the Saints’ rookie minicamp press conference. He was moved after the Saints’ drafted Patrick Robinson in the first round of the 2010 NFL Draft. With the addition of Robinson, Jenkins would’ve entered camp as the fifth cornerback on the roster behind Jabari Greer, Tracy Porter, Randall Gay, and Patrick Robinson. During training camp, he competed to be a backup safety against Usama Young. Head coach Sean Payton named Jenkins the starting free safety to start the season after Darren Sharper underwent microfracture surgery and was placed on the physically unable to perform list.

On October 3, 2010, Jenkins recorded four solo tackles and made his first career sack on quarterback Jimmy Clausen during a 16–14 win against the Carolina Panthers in Week 4. In Week 7, he collected a season-high nine combined tackles in the Saints’ 30–17 loss to the Cleveland Browns. He was inactive for the Saints’ Week 11 victory against the Seattle Seahawks due to a neck injury he sustained the previous game. On November 25, 2010, Jenkins recorded four combined tackles and made a key play in the fourth quarter to spark a comeback by the Saints in a 30–27 victory over the Dallas Cowboys in Week 12. Jenkins forced a fumble by wide receiver Roy Williams and recovered it with less than 3:20 remaining and the Saints down 27–23. Saints’ head coach Sean Payton said Jenkins performed “one of those plays that inspires everybody on the team”. Jenkins was named NFC Defensive Player of the Week for his performance. In Week 14, he made four solo tackles, three pass deflections, two interceptions, and his first career touchdown during a 31–13 victory against the St. Louis Rams in Week 14. He returned an interception by Sam Bradford for a 96-yard touchdown in the third quarter. Jenkins received NFC Defensive Player of the Week honors for the second time in 2010 for his performance. Jenkins injured his knee in the Saints’ Week 17 loss to the Tampa Bay Buccaneers and was forced to miss the NFC Wildcard Game. He finished his first season as a safety with 64 combined tackles (54 solo), 12 pass deflections, two interceptions, a forced fumble, a fumble recovery, a sack, and a touchdown in 15 games and 15 starts.

In Week 8, Jenkins recorded five solo tackles, a pass deflection, and sacked quarterback Sam Bradford in the Saints’ 31–21 loss at the St. Louis Rams. On December 11, 2011, Jenkins collected a season-high ten combined tackles (eight solo) during a 22–17 victory at the Tennessee Titans in Week 14. Jenkins was inactive in Week 17 and was rested by head coach Sean Payton as the Saints had already clinched a playoff berth with a 12–3 record. Jenkins completed the 2011 season with 77 combined tackles (63 solo), nine passes defensed, and a sack in 15 games and 15 starts.

The New Orleans Saints finished first in the NFC South with a 13–3 record. On January 7, 2012, Jenkins started his first career playoff game and recorded five combined tackles during a 45–28 win against the Detroit Lions in the NFC Wildcard Game. The following week, he started in the NFC Divisional Round and made eight solo tackles, a pass deflection, and sacked quarterback Alex Smith in the Saints’ 36–32 loss.

On November 5, 2012, he collected a season-high 13 combined tackles (seven solo) in the Saints’ 28–13 victory against the Philadelphia Eagles in Week 9. In Week 11, Jenkins recorded six combined tackles, broke up a pass, and returned an interception for a touchdown during a 38–17 victory at the Oakland Raiders. He returned an interception by quarterback Carson Palmer, that was intended for tight end Brandon Myers, for a 55-yard touchdown in the first quarter. The touchdown was Jenkins’ second pick six of his career. Jenkins was inactive for the last three regular season games (Weeks 15–17) due to a hamstring injury. Jenkins finished the 2012 season with 94 combined tackles (65 solo), seven pass deflections, an interception, and a touchdown in 13 games and 13 starts.

On October 13, 2013, Jenkins recorded eight combined tackles, a pass deflection, and earned a career-high 1½ sacks on Tom Brady during a 30–27 loss at the New England Patriots in Week 6. Jenkins was inactive for two games (Weeks 9–10) due to a back injury. In Week 13, he collected a season-high ten combined tackles (seven solo) in the Saints’ 34–7 loss at the Seattle Seahawks. He finished the 2013 season with 68 combined tackles (44 solo), six pass deflections, 2½ sacks, and two interceptions in 14 games and 14 starts.

The New Orleans Saints finished second in the NFC South with an 11–5 record and defeated the Philadelphia Eagles 26–24 in the NFC Wildcard Game. On January 11, 2014, Jenkins played in his last game as a member of the Saints and recorded five combined tackles during 23–15 loss at the Seattle Seahawks in the NFC Divisional Round.

Jenkins became an unrestricted free agent for the first time in his career in 2014. He garnered interest from multiple teams, but did not receive a contract offer from the Saints. On March 11, 2014, the Philadelphia Eagles signed Jenkins to a three-year, $16.25 million contract that included $8.50 million guaranteed.

On September 28, 2014, Jenkins recorded seven combined tackles, a pass deflection, and returned an interception by quarterback Colin Kaepernick for a 53-yard touchdown during a 26–21 loss at the San Francisco 49ers in Week 4. The pick six marked his third touchdown of his career and was his third consecutive game with an interception. In Week 15, he collected a season-high eight solo tackles in the Eagles’ 38–27 loss to the Dallas Cowboys. Jenkins finished the 2014 season with 80 combined tackles (64 solo), 15 passes defensed, three interceptions, a forced fumble, a fumble recovery, and a touchdown in 16 games and 16 starts.

Jenkins returned as the starting free safety in 2015 and played alongside strong safety Walter Thurmond. On October 25, 2015, he made a season-high ten combined tackles (eight solo) and broke up a pass during a 20–19 loss to the Miami Dolphins in Week 10. On December 6, 2015, Jenkins recorded seven combined tackles, deflected a pass, and returned an interception for a touchdown in the Eagles 35–28 victory at the New England Patriots in Week 13. He intercepted a pass by quarterback Tom Brady, that was thrown to Danny Amendola at the goal line, and returned it for a 99-yard touchdown in the third quarter. It became Jenkins fourth career pick six and his performance earned him NFC Defensive Player of the Week. On December 28, 2015, the Philadelphia Eagles fired head coach Chip Kelly after finishing Week 16 with a 6–9 record. Jenkins finished his second and last season under defensive coordinator Billy Davis with a career-high 109 combined tackles (90 solo), ten pass deflections, two interceptions, three forced fumbles, and a fumble recovery in 16 games and 16 starts. Pro football focus gave Jenkins an overall grade of 85.8, which ranked second among all qualifying safeties in 2015. On January 25, 2016, Jenkins announced via Twitter that he was added to the 2016 Pro Bowl after originally being named a seventh alternate.

On February 22, 2016, the Philadelphia Eagles signed Jenkins to a four-year, $35 million contract extension with $16 million guaranteed and a signing bonus of $7.50 million. Jenkins also had a year remaining on his previous contract from 2014. In total, Jenkins is due $40.50 million over the next five seasons (2016–2020).

The Philadelphia Eagles’ new head coach Doug Pederson retained Jenkins as a safety, alongside Rodney McLeod. In Week 2, he collected five combined tackles, deflected a pass, and sacked quarterback Jay Cutler during a 29–14 win at the Chicago Bears. On October 16, 2016, Jenkins recorded six combined tackles, two pass deflections, and returned an interception for a touchdown in the Eagles’ 27–20 loss at the Washington Redskins in Week 6. He intercepted a pass by Kirk Cousins that was initially intended for tight end Vernon Davis and returned it for a 64-yard touchdown in the second quarter. On December 22, 2016, Jenkins made six combined tackles, a season-high three pass deflections, intercepted two passes, and returned one for a touchdown in a 24–19 victory against the New York Giants in Week 16. He intercepted a pass by quarterback Eli Manning originally intended for tight end Will Tye and returned it for a 34-yard touchdown in the first quarter. It became Jenkins’ sixth pick six of his career. Jenkins completed the 2016 season with 72 combined tackles (47 solo), nine passes defensed, three interceptions, two touchdowns, and a sack in 16 games and 16 starts. He was ranked the 90th best player in the league on the NFL Top 100 Players of 2017.

On September 19, 2016, Jenkins began raising his fist during the national anthem to bring attention to racial inequality and continued to do it every week throughout 2016 and 2017. He said he would not stop protesting during the national anthem even if the NFL or his team’s owner prohibited players from doing so. Jenkins has met on Capitol Hill with legislators, written an opinion-editorial in The Washington Post and signed a letter to NFL commissioner Roger Goodell explaining his perspective on the issues.

Defensive coordinator Jim Schwartz retained Jenkins and Rodney McLeod as the starting safety duo to begin the 2017 season. In Week 7, Jenkins collected a career-high ten solo tackles and a sack during a 34–24 win against the Washington Redskins. In Week 12, he made two combined tackles, a pass deflection, and an interception during a 31–3 victory against the Chicago Bears. It marked Jenkins’ second consecutive game with an interception. On December 19, 2017, it was announced that Jenkins was voted to the 2017 Pro Bowl. (He was unable to participate because the Eagles played in the Super Bowl.) He finished the 2017 season with 76 combined tackles (63 solo), eight pass deflections, two interceptions, and a sack in 16 games and 16 starts. Pro Football Focus gave Jenkins an overall grade of 84.2, which ranked 19th among all qualifying safeties in 2017. He was ranked 96th by his peers on the NFL Top 100 Players of 2018.

The Philadelphia Eagles finished first in the NFC East with a 13–3 record and received a first round bye and home-field advantage throughout the playoffs. The Eagles advanced to the Super Bowl after defeating the Atlanta Falcons 15-10 in the NFC Divisional Round and the Minnesota Vikings 38–7 in the NFC Championship Game. On February 4, 2018, Jenkins started in Super Bowl LII and recorded four solo tackles and a pass deflection as the Eagles defeated the New England Patriots 41–33. The victory in Super Bowl LII marked Jenkins’ second Super Bowl victory and became the second time he helped a team achieve its first Super Bowl win in franchise history.

The Eagles declined to pick up Jenkins’ contract option for the 2020 season, making him a free agent at the start of the new league year on March 18, 2020.

On March 23, 2020, Jenkins signed a four-year, $32 million contract to return to the New Orleans Saints.

On June 4, 2020, Jenkins posted an Instagram video in response to Drew Brees’s comments that criticized protests during the National Anthem.

In July 2020, Jenkins received backlash after issuing a message that was seen by many in the Jewish community as dismissive in response to DeSean Jackson posting anti-semitic posts on his Instagram account that included a quote falsely attributed to Adolf Hitler. Jenkins said that Jackson’s posts were a “distraction” and that “Jewish people aren’t our problem.”