During his freshman season at Ohio State Jenkins spent most of his time at nickelback. 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.
Jenkins is a member of the Omega Psi Phi fraternity. He was vice president, stepmaster, and chaplain of the Ohio State chapter; he has a prominent fraternity brand on his upper left arm, and another one on his chest.
Jenkins was considered one of the top-2 defensive backs available in the draft (alongside Vontae Davis), and drew comparisons to Terence Newman. However, after Jenkins ran a comparably slow 40 yard dash, some scouts considered him better suited for the safety position. He was drafted by the Saints, 14th overall.
Jenkins was the first cornerback to be taken by the Saints in the first round since Oregon's Alex Molden went at No. 11 in the 1996 NFL Draft. On August 9, 2009, the Saints agreed to terms with Jenkins on a five-year, $19 million contract.
Jenkins was moved to free safety for the 2010 season, originally with the intent of backing up starting free safety Darren Sharper; he became a starter after Sharper was placed on the Physically Unable to Perform ("PUP") list to start the season, and continued to receive substantial playing time even after Sharper returned from his injury.
In the fourth quarter of a 2010 Thanksgiving Day game against the Dallas Cowboys, Jenkins came from behind to strip the ball from Cowboys receiver Roy Williams. The Saints were losing at that point of the game, but came back to win the game, 30-27. Saints 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. Two weeks later, Jenkins intercepted two passes from St. Louis Rams quarterback Sam Bradford, returning one of them 96 yards for his first NFL touchdown. Jenkins was again named NFC Defensive Player of the Week.
On December 6, 2015 in a game against the New England Patriots, Jenkins caught an interception from Tom Brady on the goal line and returned it 99 yards for a touchdown that helped the Eagles upset the Patriots 35-28. For his performance, Jenkins was named NFC Defensive Player of the Week for Week 13 of the 2015 season. In a defense that started to lose its spark a week after the midway point of the season, Jenkins emerged as the team's leading tackler with 109, and he also caused 5 turnovers, 2 interceptions and 3 forced fumbles. For his 2015 season, Jenkins was rated as the best strong safety in the NFL by Pro Football Focus, but he did not make the AP-All-Pro team, and he was only added to the Pro Bowl roster after starting as a 7th alternate.