Brewer joined his first band, called The Red Devils, at the age of 12. After leaving "The Red Devils", Brewer joined another band named the "Jazzmasters" for whom he played drums and sang vocals. In 1964, Brewer joined former DJ Terry Knight as well as bassist Herm Jackson, guitarist Curt Johnson, and keyboardist Bobby Caldwell and formed the band Terry Knight and the Pack. In 1967, Brewer met guitarist Mark Farner who joined the band after Johnson left.
In 1977, following the initial breakup of Grand Funk, Brewer and former Grand Funk bandmates Mel Schacher and Craig Frost formed a new band named "Flint". Flint released one self-titled album before disbanding. In 1981, Brewer and Farner resurrected Grand Funk for an album that cracked the Billboard albums chart. Two years later, they split again and Brewer joined Bob Seger's Silver Bullet Band. He also continued in other musical endeavors, including producing for the band The Godz. In 1996 Brewer, Schacher, and Farner reunited as Grand Funk, and were eventually named one of Pollstar's top-grossing acts of 1998. Farner decided to leave the band at the end of 1998 to resume his solo career. In 2000, Brewer and Schacher added vocalist Max Carl, former KISS guitarist Bruce Kulick and keyboardist Tim Cashion to the line-up.
Brewer played the bongo on Frank Zappa's song 'Let me take you to the beach' from the album Studio Tan, released in 1978 Brewer was featured in Classic Rock Drum Solos, performing a solo from when he and Grand Funk Railroad sold out Shea Stadium in 1971. In 2000, Don performed as a guest clinician at Modern Drummer Magazine's annual Drum Festival event, where he was honored as one of the most influential drummers in the history of rock. In 2006 Brewer rejoined the Silver Bullet Band for their 2006–07 tour; it was his first appearance with the band since he played for them on their 1983 tour. He also played with them on Seger's 2011 tour. He is also playing drums during Bob Seger's 2014 "Ride Out" concert tour throughout the United States.