The early part of Newsted’s music career had him performing bass for Flotsam and Jetsam on their 1986 album Doomsday for the Deceiver. Newsted wrote the majority of lyrics for the album.

On September 27, 1986, during the European leg of the Damage, Inc. Tour, Metallica’s bassist Cliff Burton died when the band’s tour bus crashed. Following Burton’s death, the group began a search for a new bassist. They considered and auditioned over 50 musicians, including Greg Christian of Testament, Gene Gilfen of Blind Illusion, Mel Sanchez of Abbatoir, Mike Jastremski of Heathen, Troy Gregory, Les Claypool, David Ellefson of Megadeth and various others. Newsted was the last in line and ended up winning the part. He said in a 2015 interview that he learned about Metallica’s plan to open for Ozzy Osbourne’s tour at the time. To his advantage, Newsted strategically procured the band’s setlist, studied it, and presented it to drummer Lars Ulrich saying he knew all these songs, much to Ulrich’s surprise. Two days later, Metallica invited Newsted back and announced to him that he had been chosen to fill the bassist position. The band involved both of Burton’s parents in the decision to choose Newsted. Burton’s parents were present during the announcement. After the band broke the news to Newsted, Burton’s mother hugged him tightly and said, “You are the one. Please, be safe.”

Newsted’s first live performance with Metallica was at the Country Club in Reseda, California, November 8, 1986. His studio debut with Metallica was on The $5.98 E.P. – Garage Days Re-Revisited in 1987. This was followed by his first studio album with the band, …And Justice for All (1988), which was criticised for its murky bass sound. Newsted claims this was deliberate on the part of Lars Ulrich and James Hetfield, although both Ulrich and Hetfield claim they were also disappointed with the production of the album. They claim that most or all of Newsted’s bass lines closely followed the rhythm guitar lines to the point of being indiscernible from each other. However, Steve Thompson, who mixed the album, claims that Ulrich was to blame for the inaudible bass and unusual drums. Thompson wanted to be relieved of his mixing duties when Ulrich presented his ideas on the production, but Thompson was not allowed to leave and received the majority of the criticism for the poor sound quality of the record. Nonetheless, the album peaked at number 6 on the Billboard 200 and projected the band to higher success.

During his time in Metallica, Newsted also sang backing vocals on a number of Metallica songs. During tours, beginning in 1989, he would often sing parts of “Creeping Death”, “Whiplash” and “Seek & Destroy”, and he performed lead in most songs for three shows at the Summer Sanitarium Tour where Hetfield was recovering from injury.

Newsted also performed on the self-titled album Metallica (1991), which is the best-selling Metallica album to date, as well as on Load (1996), ReLoad (1997), and Garage Inc (1998). The live concert releases Live Shit: Binge & Purge and Cunning Stunts, produced in 1993 and 1997 respectively, also featured Newsted, as did the live album S&M in 1999. Newsted also played bass on the song “I Disappear” in 2000, his last studio appearance.

Recording of Load and Reload begun in 1996 and 1997 respectively and in an interview with Bass Player Magazine 1996. Newsted again stated he used the NS-2 and a few other instruments to record.

Many of which are seen in the 1997 live show Cunning Stunts. the full list of Sadowsky basses are as follows;

The Sadowsky basses were used to record Garage Inc. In 1998 and played on the Symphony and Metallica show in 1999.

He performed his last live show as Metallica’s bassist on November 30, 2000, at the My VH1 Music Awards.

During a meeting between the members of Metallica in January 2001, Newsted proposed that the band should take a year-long hiatus, and he would use that time to focus on his side-project Echobrain. When the other band members rejected Newsted’s proposals, he chose to quit the band. On January 17, as plans were being made for the band to enter the recording studio to record its eighth studio album, Newsted announced his departure. Newsted’s statement revealed his departure was based on “private and personal reasons and the physical damage I have done to myself over the years while playing the music that I love.” During a Playboy interview with Metallica, Newsted revealed that he wanted to release an album with Echobrain. Hetfield was against the idea and said, “When someone does a side project, it takes away from the strength of Metallica.” Newsted countered his statement by citing Hetfield’s contributions to other musical outlets. Hetfield replied, “My name isn’t on those records, and I’m not out trying to sell them,” and pondered questions such as Where would it end? Does he start touring with it? Does he sell shirts? Is it his band? Newsted’s departure from Metallica, along with Hetfield’s decision to go to rehab a few months later, almost led to a breakup of the band. After Hetfield rejoined Metallica, the band finished recording St. Anger, with record producer Bob Rock filling the bass slot. Robert Trujillo became the band’s new bassist in 2003.

Newsted joined Canadian thrash metal band Voivod in 2002. Coincidentally, he was also Trujillo’s replacement in Osbourne’s band during Ozzfest 2003, which included Voivod as a Second Stage act. During an MTV interview, both Osbourne and Newsted showed enthusiasm in writing an album together, with Osbourne comparing Newsted to “a young Geezer Butler”. However, this would not come to fruition as Newsted left Osbourne upon finishing tour duties in late 2003. He would soon be replaced by Rob Zombie bassist Rob “Blasko” Nicholson.

In 2004, Newsted signed on as an official supporter of Little Kids Rock, a non-profit organization that provides free musical instruments and instruction to children in underserved public schools throughout the United States.

The fourth incarnation of Voivod featured three of the four founding members: Denis Bélanger (vocals), Denis D’Amour (guitar), and Michel Langevin (drums), with Newsted on bass guitar. D’Amour died at the age of 45 on August 26, 2005, due to complications from colon cancer. The record Katorz (a phonetic spelling of quatorze, the French word for fourteen), released in July 2006, was based around riffs found on D’Amour’s laptop. A December 2008 update on Voivod’s website noted that Newsted played “all the bass tracks” on their latest album Infini, which was released on June 23, 2009. Since then, Voivod reunited with their original bass player, Jean-Yves Thériault (Blacky), for a short period of time before he would leave the band permanently.

Newsted focused on Voivod. They recorded two albums before Newsted’s participation in Rock Star Supernova, a supergroup created through reality television series Rock Star: Supernova in 2006.

Supernova formed the basis of the second season of the CBS television program Rock Star in the quest to find a lead singer. The show began online on the Rock Star website on MSN on Monday, July 3, 2006 with an Internet exclusive weekly episode, and premiered on CBS on that Wednesday, July 5. Votes were cast via the website. On September 13, 2006, Lukas Rossi was crowned the winner.

On October 23, 2006, Newsted was injured while attempting to catch a falling bass amp head (which, according to him, was the bass amp that was used to record Metallica, Load, and Reload). The accident resulted in a torn anterior labrum in his left shoulder and a rotator cuff and biceps tear in the right. He was scheduled for immediate surgery, and underwent a lengthy rehab process. During this time he was unable to play, and began to express himself through painting. On January 4, 2007, he was back playing his bass again.

Newsted has stated that he has never regretted leaving the band. In a 2009 interview, he said “I tell you very honestly, one billion percent, I have never regretted leaving Metallica. It was the right thing for everyone. It was the right thing to do for the camp. That’s it. I’ve never told anyone that I wanted to go back or anything like that—not once. I made up my mind. It was not an easy thing to do, but it was something I had to do. I thought about it very much before I pulled the trigger and because of that, I have never looked back. The past is where it’s supposed to be.” It was mentioned in the film Metallica: Some Kind of Monster that there was a rumor that Newsted would possibly rejoin the band, but to date it has not happened.

Despite his departure from Metallica, Newsted remains close with the other band members. On April 4, 2009, Newsted joined Metallica for its induction into the Rock and Roll Hall of Fame in Cleveland, Ohio. He also performed three songs at the event—”Master of Puppets”, “Enter Sandman”, and “Train Kept A-Rollin'”—with Hetfield, Ulrich, Hammett, and Robert Trujillo, and Jeff Beck, Jimmy Page, Joe Perry, Ron Wood, and Flea. On December 5, 7, 9 and 10, 2011, Newsted reunited with Metallica during all four of their 30th anniversary shows and performed several songs with the band, Trujillo and, in some cases, other guest musicians. Hetfield noted how the fans “lit up” as Newsted walked on stage, smiling and waving to the crowd.

On April 4, 2009, Newsted was present with his former Metallica bandmates James Hetfield, Lars Ulrich and Kirk Hammett, as well as Ray Burton, the father of former Metallica bassist Cliff Burton. He performed with the band alongside current bassist Robert Trujillo at the Rock and Roll Hall of Fame induction ceremony in Cleveland, Ohio. It was his first performance with the band in nearly a decade, their last performance together having taken place during the VH-1 Awards at the Shrine Auditorium in November 2000. Both Newsted and Trujillo performed onstage at the same time, which was a first for the band.

While recovering from his shoulder injury, Newsted found solace through painting. Newsted has turned out a number of large original works of art over the last half a decade. Newsted says that he went “from making crazy and colorful music to making crazy and colorful paintings.” His first gallery show opened on May 4, 2010, at Micaëla Gallery in San Francisco.

In October 2010 it was announced that Newsted would be joining a supergroup with singer Ian Gillan and former keyboardist Jon Lord from Deep Purple, guitarist Tony Iommi from Black Sabbath, second guitarist Mikko Lindström from HIM and drummer Nicko McBrain from Iron Maiden. The band, called WhoCares, recorded a charity single titled “Out of My Mind”. The charity single also features a track titled “Holy Water” and is available as digital download or CD format as of May 6, 2011.

In December 2012, Newsted announced that he had formed his own band called Newsted with drummer Jesus Mendez Jr. and guitarist Jessie Farnsworth, with Staind guitarist Mike Mushok joining later in March 2013. The band released a four-song EP, titled Metal, on January 8, 2013. Newsted released its debut album entitled Heavy Metal Music on August 6, 2013. In September 2014, the band appeared inactive as its website contained only a brief message that as of September 15, 2014, Jason Newsted was no longer on any social networking sites. As of 2018, the Newsted official website has been deactivated.

He is married to Nicole Leigh Smith, whom he wed in October 2012. She was his girlfriend of 11 years, to whom he refers as the “love of my life”. While still his girlfriend, it was Nicole, an artist herself, who suggested he try painting. She now encourages Newsted to “move forward with his art”.

On December 16, 2013, Newsted expanded upon previous statements regarding his departure from Metallica and cited that his project with Echobrain was being discouraged by James Hetfield because Metallica’s management at Q Prime wanted to go ahead with promoting Echobrain but was forced to drop it by Hetfield’s demands with the quote “other arrangements can be made”. Newsted was sure that Echobrain would not affect Metallica, explaining “And so they had told me, pretty convincingly, ‘This is a great record, we’ve been playing it around the office, that’s all I’ve been hearing, it’s fantastic, this kid has a great voice. Let’s do something with this.’ That’s what they told me, and then James Hetfield heard about it and was not happy. He was, I think, pretty much out to put the kibosh on the whole thing because it would somehow affect Metallica in his eyes, because now the managers were interested in something I was doing that had nothing to do with him”. Newsted sums up the situation as follows: “I have no idea what [Hetfield] was thinking, other than just protecting what he valued, just like he does; that’s his thing. He protects what he loves, squeezes it too hard, like he said himself. Squeeze it too hard, protecting it too much. That’s where I was coming from. The people that I had counted on for 15 years to help me with my career, help Metallica, take care of my money, do all of those things, told me, ‘Your new project is fantastic, we’d like to help you with it.’ James heard about it, the manager calls me back a couple of days later – ‘Sorry we’re not going to be able to help you with that Echobrain thing’.”

In August 2016 after being out of the public eye for two years, Newsted announced he had formed a new acoustic group named Jason Newsted and the Chophouse Band, and had scheduled several performing dates throughout the fall. A fan-made video showed the band (with Newsted on acoustic guitar and lead vocals) playing the Woody Guthrie classic “This Land Is Your Land.”