[1] On the track team, Jack earned a fourth-place finish in the 400-meter dash at the 2013 WA 3A State Meet, recording a personal best time of 49.05 seconds.

[1][6][7] Jack did not play at running back until the ninth game of the season in a 31–26 win over Arizona, when he gained 120 yards on six carries, including a 66-yard touchdown.

[7] On September 22, 2015, during a routine practice, Jack tore the meniscus in his knee while performing a non-contact drill, and a statement was released from coaches stating that he would not return for the remainder of the season.

[19][20] On October 6, head coach Jim Mora announced that Jack had withdrawn from UCLA to focus on his rehabilitilation and entering the 2016 NFL draft.

[21] His injury had occurred two days before the start of the fall quarter, and he had already fallen behind in his classes while rehabbing from his knee and coping with his short-term immobility.

[24] Throughout the draft process, Jack attended private visits and workouts with multiple NFL teams, including the Jacksonville Jaguars, Miami Dolphins,[25] Chicago Bears,[26] New Orleans Saints,[27] San Francisco 49ers,[28] Atlanta Falcons,[29] and Oakland Raiders.

[31] Prior to the draft, Jack was confident he could play immediately, but admitted that his knee had degenerative aspects which could require microfracture surgery in the future.

[34] He was ranked the top linebacker prospect in the draft by Sports Illustrated, ESPN, and NFL analysts Charles Davis, Mike Mayock, Lance Zierlein, and Daniel Jeremiah.

[47] Head coach Gus Bradley named Jack the backup outside linebacker behind veterans Dan Skuta and Telvin Smith to begin the regular season.

[49] On October 2, 2016, Jack earned his first career start at strongside linebacker after Dan Skuta was unable to play after suffering a hip injury the previous week.

[52] Head coach Gus Bradley was fired after their Week 15 loss to the Houston Texans due a nine-game losing streak and a 2–12 record.

Jack finished his rookie season in 2016 with 24 combined tackles (18 solo), two pass deflections, and was credited with half a sack in 16 games and ten starts.

[55] On April 18, 2017, it was announced by the Jaguars' coaching staff that Myles Jack would enter organized team activities as the starting middle linebacker and Paul Posluszny would take over the starting strongside linebacker role previously held by Jack and the recently departed Dan Skuta.

[57] Jack reverted to his strongside linebacker position after he struggled to adjust to his new role and had difficulty performing the required duties during the Jaguars' first preseason game against the New England Patriots.

In Week 7, he collected eight combined tackles, broke up a pass, and sacked Jacoby Brissett as the Jaguars' routed the Colts 27–0.

[61] The Jaguars finished first in the American Football Conference (AFC) South with a 10–6 record in their first season under head coach Doug Marrone.

[62] On January 7, 2018, Jack started his first career playoff game and recorded six combined tackles, two pass deflections, and a sack in a 10–3 victory over the Bills in the AFC Wild Card Round.

[63] The following week, he made six combined tackles, deflected a pass, and an interception during a 45–42 win at the Pittsburgh Steelers in the AFC Divisional Round.

[65] He was a part of a controversial play in the fourth quarter that occurred after he forced a fumble by Patriots' running back Dion Lewis and recovered it.

[80] In early August 2023, Jack revealed in an interview that he considered going to trade school in order to pursue a career as an electrician or a plumber during the 2023 offseason before he signed with the Eagles.