[11] On March 18, 2013, Jefferson attended Oklahoma's pro day, but only performed the short shuttle and three-cone drill due to his hamstring injury.

[12] His character came into question after WalterFootball.com released a scouting report stating it received information from reliable sources that he had practice habits and an attitude, but was quickly dismissed after teammates and coaching staff at Oklahoma refuted the claims.

[16] Throughout training camp, Jefferson competed for a roster spot as a backup safety against Jonathon Amaya, Curtis Taylor, Javon Harris, and Josh Hill.

[22][23] On August 17, 2013, Jefferson recorded five combined tackles and intercepted two passes by Alex Tanney and Kyle Orton during a 12–7 victory against the Dallas Cowboys in their second preseason game.

[24] Head coach Bruce Arians named Jefferson the backup strong safety, behind Yeremiah Bell, to begin the regular season after he performed well in the preseason and recorded 14 combined tackles (13 solo), two interceptions, and a sack.

[29] During OTA's and training camp, Jefferson competed against Rashad Johnson and rookie first round pick Deone Bucannon for the job as the starting strong safety.

[32] In Week 3, Jefferson made ten combined tackles (eight solo) and his first career sack on quarterback Colin Kaepernick during a 23–14 victory against the San Francisco 49ers.

[33] On October 26, 2014, he collected a season-high 12 combined tackles (11 solo) and broke up a pass in the Cardinals' 24–20 victory against the Philadelphia Eagles.

[34] Jefferson was replaced as the starting free safety prior to Week 10, after Tyrann Mathieu fully recovered from his knee injury.

[34] Jefferson filled in at starting free safety for three games (Weeks 14–16) while Mathieu recovered from surgery to repair his broken thumb.

[34] Jefferson returned to training camp competing for the job as the starting strong safety against Deone Bucannon .

[39] In Week 5, he collected a season-high 12 combined tackles (eight solo), a pass deflection, and forced two fumbles in a 42–16 victory at the Detroit Lions.

[40] On November 29, 2015, Jefferson made six combined tackles and a sack on Blaine Gabbert during the Cardinals' 19–13 victory at the San Francisco 49ers.

[41][40] Jefferson finished his third season with 78 combined tackles (58 solo), five pass deflections, three forced fumbles, two sacks, two interceptions, and a touchdown in 16 games and seven starts.

On January 24, 2016, Jefferson started for the Cardinals in the NFC Championship and recorded 11 combined tackles (five solo) and a pass deflection in their 49–15 loss to the Carolina Panthers.

[46] He started the Arizona Cardinals' season-opener against the New England Patriots and recorded ten combined tackles (nine solo) in their 23–21 loss.

[47] In Week 16, he made seven solo tackles before exiting the Cardinals' 35–6 loss to the Seattle Seahawks in the second quarter after he sustained a knee injury while covering a punt.

Head coach John Harbaugh officially named him the starter to open the season, alongside free safety Eric Weddle.

Jefferson started the Baltimore Ravens' season-opener against the Cincinnati Bengals and recorded nine combined tackles and a sack on quarterback Andy Dalton during their 20–0 victory.

[54] On December 10, 2017, Jefferson made a season-high 11 combined tackles (eight solo) and was credited with half a sack during a 39–38 loss at the Pittsburgh Steelers.

[55] He finished his first season with the Baltimore Ravens with 79 combined tackles (56 solo), 2.5 sacks, two pass deflections, and an interception in 16 games and 16 starts.

[59] After spending the 2020 season out of football, Jefferson was signed a one-year, $1 million contract with the San Francisco 49ers on June 7, 2021.

On May 25, 2023, Jefferson announced that he was retiring from professional football and would be re-joining the Baltimore Ravens organization in a scouting capacity.