Spencer was the defensive line coach and run-game coordinator for the New York Giants of the National Football League (NFL) from 2020 to 2021.

A native of Hartford, Connecticut, Spencer is a 1988 graduate of Bulkeley High School, where he was a teammate of future National Football League (NFL) coach Eric Mangini.

Spencer nearly landed an entry-level job with Bill Belichick and the Cleveland Browns, where Mangini was working, but the team wanted someone local.

Spencer also had success leading the special teams, mentoring All-CAA kick returner Courtney Robinson and All-America punter Brett Arnold.

[2][10] In 2011 Tim Fugger earned second team All-SEC honors, posting 8 sacks, 11.5 tackles for loss and was drafted by the Indianapolis Colts.

[11] On January 24, 2014, it was officially announced that Sean Spencer would be following James Franklin to Penn State as the defensive line coach.

[10] Prior to the official announcement, it was reported that the position was first offered to long time Penn State assistant Larry Johnson but was turned down by the coach.

[14][15] Defensive tackle Austin Johnson garnered second team All-Big Ten honors and was selected by the Tennessee Titans in the second round with the 43rd pick.

[16] Defensive tackle Anthony Zettel who finished third team All-Big Ten was selected in the sixth round by the Detroit Lions with the 202nd pick.