While still a student at Castro Valley High School, Burton formed his first band called EZ-Street. The band took its name from a Bay Area topless bar. Other members of EZ-Street included future Faith No More guitarist “Big” Jim Martin as well as Faith No More and Ozzy Osbourne drummer Mike Bordin. Burton and Martin continued their musical collaboration after becoming students at Chabot College in Hayward, California. Their second band, Agents of Misfortune, entered the Hayward Area Recreation Department’s Battle of the Bands contest in 1981. Their audition was recorded on video and features some of the earliest footage of Burton’s playing style. The video also shows Burton playing parts of what would soon be two Metallica songs: his signature bass solo, “(Anesthesia) – Pulling Teeth”, and the chromatic intro to “For Whom the Bell Tolls”. Burton joined his first major band, Trauma, in 1982. Burton recorded the track “Such a Shame” with the band on the second Metal Massacre compilation.

In 1982, Trauma traveled to Los Angeles to perform at the Whisky a Go Go. Among those in attendance were James Hetfield and Lars Ulrich, both members of Metallica, which had formed the previous year. Upon hearing, as Hetfield described it, “this amazing shredding” (which later became “(Anesthesia) – Pulling Teeth”), the two went in search of what they thought was an amazing guitar player. When they learned that what they had heard was a bass solo by Burton, they decided to recruit him for their own band. They asked him to replace departed bassist Ron McGovney, and since Burton thought that Trauma was “starting to get a little commercial”, he agreed. The idea of having to move to Los Angeles did not sit well with him, and said he would join only if the band would relocate from Los Angeles to his native San Francisco Bay Area. Metallica, eager to have Burton in the band, left their origin of Los Angeles to make a home in El Cerrito, a town located across the bay from San Francisco.

Metallica’s debut album, Kill ‘Em All, was originally intended to inherit the name of one of their earlier demo releases (predating Burton’s participation), which was Metal Up Your Ass, but the record company did not like the title and insisted on changing it. After the band learned of the change, Burton said “We should just kill ’em all, man,” which gave the band members an idea for the new title. The album was released on July 25, 1983 through Megaforce Records.

Burton’s final performance was in Stockholm, Sweden, at the Solnahallen Arena on September 26, 1986, one day before his death. The final song he performed was “Fight Fire With Fire”.

On October 3, 2006, a memorial stone was unveiled in Sweden near the scene of the fatal crash. The lyrics “…cannot the Kingdom of Salvation take me home” from “To Live Is to Die” are written on Burton’s memorial stone.

On April 4, 2009, Burton was posthumously inducted into the Rock and Roll Hall of Fame, with fellow Metallica bandmates James Hetfield, Lars Ulrich, and Kirk Hammett. Future bassists Jason Newsted and Robert Trujillo were inducted as well. During the ceremony, the induction was accepted by his father Ray Burton, who shared the stage with the band and said that Cliff’s mother was Metallica’s biggest fan.

A biography, To Live Is to Die: The Life and Death of Metallica’s Cliff Burton, written by Joel McIver, was published by Jawbone Press in June 2009. Hammett provided the book’s foreword.

In January 2013, the guitar manufacturer Aria revealed through Metallica’s official website that it would be releasing a replica of Burton’s bass, called the Aria Pro II Cliff Burton Signature Bass. The company had received permission from Burton’s family and from Metallica to produce the instrument. The bass guitar was officially unveiled at Winter NAMM in Anaheim, California. On January 25, 2013, Burton’s father Ray attended the press conference where he signed autographs and talked about Burton’s life and the instrument. Current Metallica bassist Robert Trujillo was also present and was the first to try out the bass, playing parts of “(Anesthesia) – Pulling Teeth”. It is unknown whether any other members of Metallica attended the event. Ray Burton said, “What a beautiful instrument and a wonderful tribute to Cliff.”

In November 2016, Metallica released the album Hardwired… to Self-Destruct. The deluxe version of the album features a series of live recordings at Berkeley, California’s legendary record store Rasputin Music in celebration of Record Store Day on April 16, 2016. The song “Fade to Black” was played with lead singer James Hetfield dedicating the song to Burton. During the song Hetfield yells, “Can you hear us Cliff?”.

In 2017, it was revealed that Burton’s parents had been donating his posthumous royalty payments to a scholarship fund for music students at his alma mater Castro Valley High School.

In 2018, the Alameda County, California, Board of Supervisors issued a proclamation declaring February 10, 2018 (what would have been Burton’s 56th birthday) as “Cliff Burton Day” after a fan petition successfully passed.

The S&M2 concert in 2019 featured San Francisco Symphony bassist Scott Pingel paying tribute to Burton by playing his signature bass solo, “Anesthesia (Pulling Teeth)”, using an electric double bass with pedal effects.