At the age of fifteen, Hoppus got his first bass from his father after helping him paint his house. Mark played bass and sang in the band Pier 69, primarily covering songs by The Cure. He also played in a band called The Attic Children in 1988. He later moved to San Diego, where he met Tom Delonge (another blink-182 member) through his younger sister, Anne Hoppus. Delonge was a friend of Anne's boyfriend, Kerry Key, and constantly complained about wanting to join a band. She finally introduced Hoppus and Delonge in August 1992.

Hoppus and Delonge, with their friend, drummer Scott Raynor, decided to form a band in 1992. They were under the name "Duck Tape" until their third show, when Delonge said he liked another name..."blink", but an Irish techno band was already using that name and threatened them with a court case, so they changed their name to blink-182. In 1997, after the release of their fourth album Dude Ranch, blink-182 went on tour with The Aquabats (whose drummer at the time was Travis Barker). Scott's dismissal from blink-182 was rumored to come when he did not show up for two weeks of shows because of a drinking problem. Travis performed instead, and when Raynor returned, he felt awkward and decided to leave the band completely. Barker learned the entire setlist in about two hours before a show, and eventually left The Aquabats to become the band's full-time drummer.

In 1999, they released their first album with Barker, Enema of the State. They later released two more studio albums, Take off Your Pants and Jacket and an untitled album (usually referred to as blink-182).

Hoppus provided backing vocals on MxPx's eighth studio album Panic for the song "Wrecking Hotel Rooms." He is currently working on a side project with Travis Barker and Carol Heller - an electronica band called Plus-44; their first album is expected some time in Summer 2006. In 2005, Mark created a podcast called "Hi, My Name Is Mark" - every two weeks, Mark plays songs by underground bands, interviews his favorite artists and reminisces about happenings in his life. Mark talked about the podcast in the April issue of Alternative Press stating he would love to one day post some of Plus-44's music on the podcast.

Hoppus married his girlfriend, Skye Everly, on December 2, 2000. Their son, Jack Hoppus, was born on August 5, 2002.

Mark also co-owns the popular punk clothing company, Atticus, and is a record producer. He produced the second album of Minnesota band Motion City Soundtrack, Commit This to Memory. He also provided backing vocals for the song "Hangman" on this album.

He also has a signature series bass, the Mark Hoppus Fender Jazz Bass. Early in his carrer he used Ernie Ball Music Man basses. He has been seen using other kinds of Fender jazz basses in shows but primarily he uses his signature series.