Keenan was born in Oxford, Mississippi but now lives in New Orleans, where he owns a bar named "Le Bon Temps Roule." His father, a former musician, is a local real estate appraiser in New Orleans. While developing his playing style in New Orleans, Pepper served as a member of local band Graveyard Rodeo, and met and became friends with Corrosion of Conformity during their frequent shows at the infamous Franklin Avenue VFW Hall in New Orleans. Keenan became the father of a daughter named Flannery Rose Keenan, with his longtime girlfriend Anna Hrnjak on January 5, 2010. In an interview with Guitar.com, Keenan was asked about his thoughts on politics in which he responded "I mean, the Bible means a lot more to me than the Constitution and any fuckin' politics involved in this country or any other country."
Keenan joined Corrosion of Conformity in 1989. Corrosion of Conformity released their third album called Blind with Keenan on rhythm guitar. After Karl Agell and Phil Swisher left the band (Swisher being replaced by original bassist Mike Dean), Keenan took over on vocals and guitar. Corrosion of Conformity have since released the albums Deliverance, Wiseblood, America's Volume Dealer, and In the Arms of God, as well as the live release, Live Volume. From 2006 to 2010, Corrosion of Conformity had been on hiatus. The band has since reunited and recorded an album without Keenan. However, a possibility of Keenan re-joining C.O.C. remains, according to a message dated May 15, 2010, on the official C.O.C. website. According to drummer Reed Mullin, Corrosion of Conformity plans to reunite with Keenan in 2015 for a new album and tour. Corrosion of Conformity performed their first show with the re-united Deliverance era line-up of Pepper Keenan, Woody Weatherman, Mike Dean, and Reed Mullin on Marcy 7, 2015 in Manchester, Mexico. Their first U.S. tour with the re-united line-up, supporting Clutch, was announced on July 28, 2015.
Keenan plays guitar and sings a part of the second verse on Metallica's cover of the Lynyrd Skynyrd song "Tuesday's Gone". He also recorded a number of other songs in the same session, but this was the only one given a general release (on the album Garage Inc.), the others only being available as bootlegs. Keenan is good friends with lead singer and guitarist James Hetfield. Hetfield provided backing vocals on "Man or Ash" from Corrosion of Conformity's Wiseblood. Keenan auditioned for Metallica's vacant bass player position following Jason Newsted's departure from the band but lost out to former Suicidal Tendencies/Ozzy Osbourne bassist Robert Trujillo. Keenan's audition is shown in the Metallica documentary Some Kind of Monster. In addition to his contribution to the song "Tuesday's Gone" Pepper also appeared with Metallica onstage at the Download Festival in Donington, England in 2006 along with Matt Heafy of Trivium to provide additional vocals on the song "Die, Die My Darling" (a Misfits cover). This song was played at the end of Metallica's headlining set.