After the departure of Kimo von Oelhoffen via free agency for the New York Jets in March 2006, Keisel signed a new four-year contract with the Steelers, worth a reported 14 million dollars.

[7] That season, he won the starting position at right defensive end and played in all 16 games making 55 tackles and 5.5 sacks, a career-high.

[11] At the end of the 2010 season, Keisel and the Steelers appeared in Super Bowl XLV against the Green Bay Packers.

While agent Eric Metz stated that Keisel "has every intention to continue to play football,"[15] no contract had yet been offered by the Steelers organization.

[16] In 2014, Keisel finished the season appearing in 12 games and recording eight solo tackles, nine assists, a single sack and an interception.

He researched the statistics of players that were in the NBA at the time and found that his size wouldn't compare to those playing basketball at the professional level.

Since retirement from football, Brett and his wife Sarah have been involved with numerous charitable organizations, including the Cystic Fibrosis Foundation.

[20] In 2018, Keisel was a pallbearer at the funeral of brothers Cecil and David Rosenthal, who were killed in the Pittsburgh synagogue shooting.

His beard has its own Facebook page and Twitter account and was mentioned repeatedly in the media during the Steelers' playoff run.

[24] On July 27, 2022, as a guest on Steelers' Defensive Linemen Cam Hewyard's "Not Just Football" Podcast, Keisel said that he started growing it partly due to superstition.

He followed up saying that the Pittsburgh Penguins had just recently won the Stanley Cup, and that he saw the playoff beards the players grew, and was a fan of them, and wanted to try it out.

It was announced on January 8, 2013, that "The Third Annual Shear the Beard Event" would be held on February 7, 2013, at Jergel's Rhythm Grille in Warrendale, PA, with all proceeds benefiting the cancer program at Children's Hospital.

It was announced on January 14, 2014, that "The Fourth Annual Shear the Beard Event" would be held on February 5, 2014, at Jergel's Rhythm Grille in Warrendale, PA, with all proceeds benefiting the cancer program at Children's Hospital.

Shavers such as Ben Roethlisberger, James Harrison, Cameron Heyward, and Arthur Moats have taken part in the shaving of Keisel's beard.