Upon graduating from Castro Valley High School in 1980, Burton studied music at Napa Valley Junior College in northern California. One of his fellow schoolmates was "Big" Jim Martin, former guitarist of Faith No More.

The members of Metallica were searching for a replacement to their current bassist, Ron McGovney when they attended a show by Burton's band, Trauma, and were impressed on hearing him perform his famous solo, '(Anesthesia) Pulling Teeth' with an effects pedal.

Burton was repeatedly asked to join Metallica and eventually agreed on the condition that the band would relocate from Los Angeles to the San Francisco, California Bay Area.

During their tours, Burton exposed the band to a variety of music styles ranging from The Misfits, Pink Floyd, The Velvet Underground, and Thin Lizzy, to classical pianist Glenn Gould.

Kirk Hammett said that Cliff got him into The Velvet Underground and other musicians.

Burton first appeared with Metallica at The Stone, in San Francisco, CA on March 5th, 1983. His final performance was in Stockholm, Sweden on September 26, 1986, One of Cliff's Final Preformances with the band is avalible for free to download from Metallicas website.

During the European part of the Master of Puppets tour, the band had complained that the sleeping cubicles were unsatisfactory and uncomfortable. As a minor solution the members would draw cards for the most comfortable bunk. On the evening of September 27, 1986 Burton had won the game with an ace of spades. He was sound asleep when the band's tour bus encountered a patch of black ice, skidded off of the road, and flipped over on the grass in Ljungby Municipality, rural Sweden.

Burton fell through the window of the emergency exit door and was killed instantly when the bus landed on top of him. He was crushed a second time when, in an effort to clear the accident scene, a winch cable snapped and the vehicle was dropped back onto the body.

Controversy continues to surround the cause of the crash. The driver of the bus claims to have hit black ice, however on inspecting the road for several miles following the crash, lead singer James Hetfield said he found nothing. Hetfield and other members of the band claim the driver may have been drinking.

Burton's body was cremated. At the ceremony, the instrumental 'Orion' from the album 'Master of Puppets' was played. Subsequently, Metallica did not perform this song again until June 6, 2006 (when they performed the album in its entirety to mark the 20th anniversary of its release). Until then only parts of the song had been used as part of their performance. During the 1990s, Burton's replacement, Jason Newsted, would often use the bass line as part of a medley.

Burton's work and tragic death have inspired many songs from bands including Megadeth ("In My Darkest Hour") and Primus, as well as bassists such as Billy Sheehan and John Myung.