Pagano previously served as the defensive coordinator for the Baltimore Ravens in 2011, of the Chicago Bears from 2019 to 2020, and was an assistant coach for the Oakland Raiders and Cleveland Browns.

In his five years there, he recruited and coached four first round NFL draft picks, and during the 2000 season, his secondary was named the nation's best by College Football News.

He was promoted to defensive coordinator on January 18, 2011, succeeding Greg Mattison who accepted a similar position at the University of Michigan.

New offensive coordinator Bruce Arians became the interim head coach in place of Pagano and the Colts finished 11–5, good for a 9-game turnaround over the previous year and a 5th seed playoff berth.

They were defeated by the eventual Super Bowl champion and Pagano's former team, Baltimore Ravens in the Wild Card round.

Keeping up the trend of moving forward, the Colts would defeat both the Cincinnati Bengals and Denver Broncos in the first two rounds of the playoffs, advancing to their first AFC Championship Game under Pagano.

Looking to defend their back-to-back division titles and finally advance to the Super Bowl, the Colts finished 8–8 in 2015 and missed the playoffs for the first time under Pagano.

Pagano did manage to keep the Colts in playoff contention all season, which included a league-leading 6 wins with reserve quarterbacks.

On December 31, 2017, an hour after defeating the Houston Texans 22–13 in the final game of the season, Pagano was fired after missing the playoffs for the third straight year.

On January 11, 2019, Pagano was hired by the Chicago Bears as their defensive coordinator, replacing Vic Fangio, who left to become the head coach of the Denver Broncos.

[9] The unit enjoyed early success that included limiting the Minnesota Vikings' second-ranked rushing offense to just 40 yards as the team began the year 3–1,[10] while its ten takeaways were the third most in the league by the Week 6 bye, but struggled with penalties.

[11][12] The Bears finished the year 8–8 with the eighth-ranked defense and ninth in both running and passing categories; Chicago was also fourth in total points allowed, the only team in the top five that did not reach the playoffs.

[22] The Bears ended the season 8–8 again but qualified for the playoffs; in the Wild Card Round, the defense held the New Orleans Saints to seven points in the first half before losing 21–9.

[25][26] On January 13, 2021, Pagano announced his retirement, explaining in a statement that coaching "takes a lot of time away from your family and loved ones.

[27] After making recurring appearances on The Pat McAfee Show,[28] Pagano began hosting a new segment called "Coach P's Keys" on Thursdays during the 2022 NFL season.