He was named the Defensive MVP of the 2016 College Football Playoff National Championship after recording three tackles and an interception against Clemson in a 45–40 victory.

He received an invitation to the NFL Combine, but was unable to perform any physical drills during the entire pre-draft process due to the broken leg he suffered in October.

[19] He made his first career start and professional regular season debut in the Bears' season-opener against the Atlanta Falcons and recorded three solo tackles during the 23–17 loss.

[20] On October 22, 2017, Jackson recorded four solo tackles, deflected a pass, made his first career interception, recovered a fumble, and scored two touchdowns during the Bears' 17–3 victory over the Carolina Panthers.

[21] He recovered a fumble by quarterback Cam Newton, on the Panthers' first drive, and returned it for a 75-yard touchdown in the first quarter to mark the first score of his career.

During the second quarter, Jackson intercepted a pass attempt thrown by Newton, that was intended for wide receiver Kelvin Benjamin, and returned it for a 76-yard touchdown.

In Week 2, Jackson recorded three solo tackles, one pass deflection, and made his first career sack during a 24–17 win against the Seattle Seahawks.

[29] He recorded interceptions over the next two games off Arizona Cardinals' Sam Bradford (including a pick-six that was called back for an offside penalty) and Tampa Bay Buccaneers' Ryan Fitzpatrick.

[30][31] On November 4, 2018, Jackson recorded six combined tackles and returned a fumble recovery for a 65-yard touchdown during a 41–9 victory at the Buffalo Bills in Week 9.

Jackson intercepted a pass by Vikings’ quarterback Kirk Cousins, that was intended for wide receiver Laquon Treadwell, during the fourth quarter.

[48] On Thanksgiving Day against the Lions, Jackson recorded his first interception of the season off a pass thrown by rookie quarterback David Blough with 30 seconds left in the game, sealing a 24–20 Bears' win.

[51] In week 17 against the Vikings, Jackson intercepted a pass thrown by Sean Mannion and returned it for 14 yards as time expired to seal a 21–19 Bears' win.

[52] On January 3, 2020, the Bears signed Jackson to a four-year $58.4 million contract extension, making him the highest paid safety in the NFL.

[63] Jackson suffered a season-ending Lisfranc injury during a Week 12 loss to the New York Jets and was placed on injured reserve on November 29.

[68] He, along with fellow safety Marcus Williams, performed poorly, causing the Ravens to have one of the worst passing defenses in the NFL at the beginning of the season.

[69] However, after Jackson had a horrendous performance, which included multiple dropped potential interceptions and giving up the game-winning touchdown in a 24–29 loss,[70] he himself was benched for Week 9's game against the Denver Broncos with Williams replacing him.

[71] Jackson did not travel with the team for their Week 11 game against the Pittsburgh Steelers after expressing his dissatisfaction with his reduced role;[72] he was subsequently waved on November 23.