On September 26, 2021, he tied the NFL record for the longest play with a 109 yard return off a missed field goal.

Jamal Agnew constantly stood out among his peers at Point Loma; however, due to his size, he was not offered a scholarship to any major NCAA Division I school.

[7] Following 2008 draftee Josh Johnson, he became the second player in San Diego Torrero history to be drafted.

[10] In Week 2 on Monday Night Football, Agnew scored his first NFL touchdown on an 88-yard punt return in the fourth quarter in a 24–10 win over the New York Giants, earning him National Football Conference Special Teams Player of the Week.

[11][12] In Week 6, against the New Orleans Saints, he recorded a 74-yard punt return touchdown in the fourth quarter.

[28] On September 26, 2021, the following week against the Arizona Cardinals, he scored another touchdown on a 109 yard return of a missed 68-yard field goal attempt, tying the NFL record for longest play with Antonio Cromartie and Cordarrelle Patterson, at the end of the first half in the 19–31 loss.

[32] In the Jaguars 31–30 win over the Los Angeles Chargers in the Wild Card Round of the playoffs, he returned four kickoffs for 134 yards.

[35] Agnew was named to 2023 Pro Bowl after Baltimore Ravens' kick returner Devin Duvernay was deemed unable to play due to injury.