Wilk's success as the drummer of Rage Against the Machine came from the failure of a different band; he once auditioned for a band called Lock Up, who released one album (titled Something Bitchin' This Way Comes) through Geffen records in 1989 and broke up when the album received little media attention upon release. Former Lock Up guitarist Tom Morello was looking to pick up where Lock Up left off and start a new band, and contacted Wilk, who was playing with the band Greta, to see if he was interested in playing the drums. A short while after, the duo met Zack de la Rocha, a rapper, and through de la Rocha met bassist Tim Commerford (a childhood friend of Zack's) and Rage Against the Machine was born. After frequenting the L.A. club circuit, Rage Against the Machine signed a record deal with Epic Records in 1992. That same year, the band released their self titled debut. They achieved a phenomenal amount of mainstream success and released three more studio albums.

In late 2000, de la Rocha quit the band. On September 13, 2000, Rage Against the Machine performed their last concert at the Grand Olympic Auditorium in Los Angeles, California. The remaining members formed Audioslave with former Soundgarden frontman Chris Cornell. The band released theirs selftitled debut album in 2002, which was followed by Out of Exile in 2005 and the bands final studio album Revelations in 2006. Audioslave disbanded when Cornell formally left the band in February 2007 to focus on his solo career..

From 2001 till 2007 he played in the band Audioslave.

Rumors of a Rage Against the machine reunion were first heard on January 22, 2007. On April 29, 2007, Rage Against the Machine reunited at the Coachella Music Festival. The band played in front of an EZLN backdrop to the largest crowds of the festival. The performance was initially thought to be a one-off, this turned out not to be the case. The band played 7 more shows in the United States in 2007 (including their first non-festival concert in 7 years at the Alpine Valley Music Theater in East Troy, Wisconsin), and in January 2008, they played their first shows outside the US as part of the Big Day Out Festival in Australia and New Zealand.
The band has since continued to tour around the world, headlining many large festivals in Europe and the United States, including Lollapalooza in Chicago.

Wilk and bandmate Tom Morello joined with Maynard James Keenan of Tool and Billy Gould of Faith No More to record the song "Calling Dr Love" for the 1994 Kiss tribute album Kiss My Ass. The lineup was billed as Shandi's Addiction. Wilk also contributed drums to rap group Cypress Hill's album Skull and Bones. Wilk and bassist Tim Commerford contributed in Keenan’s side project Puscifer and his album "V" Is for Vagina on the track "Momma Sed". In addition, Wilk composed the song "Snoop Bounce (Roc N Roll Remix)" for Snoop Dogg's Death Row's Greatest Hits CD.

In 2005, Wilk played the lead role in the independent short movie Sleeping Dogs Lie by writer Chumahan Bowen and director Stuart Lessner. The film also features Tool lead singer Maynard James Keenan as Deputy Lance.

Wilk played drums on Josh Homme's tracks on the soundtrack to Dangerous Lives of Altar Boys. Wilk has also performed live with band mate Tom Morello's sideproject Street Sweeper Social Club at the 2010 Coachella music and arts festival.

Wilk has also performed drums on English metal band Black Sabbath's final album 13. The album was released in June 2013. Wilk briefly played with Pearl Jam shortly after the release of their debut album Ten.

To the end of 2014 until June 2015, Brad Wilk was playing drums on tour with the Smashing Pumpkins along with Billy Corgan, Jeff Schroeder and also Mark Stoermer on bass. On 26 February 2015, while touring Australia with the band, he joined the Foo Fighters on stage at Sydney's Olympic (ANZ) stadium playing drums for a Van Halen cover Ain't Talkin' 'bout Love. On August 3, 2015, Wilk sat-in with The 8G Band on Late Night with Seth Meyers. He's also been drumming for Juliette Lewis on various tours and shows.

As of 2016, he is playing in the band Prophets of Rage, with Commerford, Morello, Chuck D, B-Real and DJ Lord.