[5] Spagnuolo remained there for eight years, appearing in Super Bowl XXXIX where they lost to the New England Patriots 24-21 who were led by quarterback Tom Brady.

[7] He spent two years in New York, and was the architect of the aggressive defensive strategy against the New England Patriots (the highest scoring offensive team in NFL history at the time) in Super Bowl XLII, which was instrumental in the close victory by the Giants.

[9] Following the Super Bowl win and a great deal of praise, Spagnuolo's name was widely circulated for open head coach positions around the NFL.

The same day, the Giants made Spagnuolo one of the highest-paid defensive coordinators in the NFL with a new three-year contract, worth roughly $2 million a year.

Spagnuolo then hired Josh McDaniels to be the team's offensive coordinator to replace Shurmur, who left for the Browns' head-coaching job.

[17][18][19] Spagnuolo was fired on January 2, 2012, after compiling a 10–38 overall record in his three seasons in St. Louis, the second-lowest winning percentage for a non-interim coach in franchise history.

[20] On January 19, 2012, Spagnuolo agreed to terms with the New Orleans Saints to become the new defensive coordinator under head coach Sean Payton, choosing this position rather than an offer from the Philadelphia Eagles.

[22][23] In 2012, the Saints allowed the most yards for a season of any defense in NFL history en route to finishing 7–9 and missing the playoffs for the first time in four years.

[29] Spagnuolo became interim head coach of the Giants after a house cleaning by the organization after the firings of McAdoo and general manager Jerry Reese on December 4, 2017.

[33][34] In the 2020 season, Spagnuolo reached his fourth Super Bowl, losing 31-9 to the Tampa Bay Buccaneers who were quarterbacked by Tom Brady.

The Chiefs defense managed to stop star running back Saquon Barkley from scoring a touchdown but could not contain quarterback Jalen Hurts despite sacking him four times.