Irons was a founding member of, and the original drummer for, The Red Hot Chili Peppers. As teenagers, Irons, Johannes, Slovak, and schoolmate Todd Strassman formed the band Chain Reaction in 1976. After its first gig, the band was soon renamed to Anthym. Slovak became dissatisfied with Strassman's bass playing and eventually taught Michael Balzary (Flea) to play bass. Flea quickly surpassed Strassman in bass skills and took over bass duties in Anthym. After graduating from high school, the band changed its name to What Is This? (which was a question often asked by people who heard the band play). Flea left the band around this time because he was offered a job playing bass in the prominent Los Angeles punk band Fear. What Is This? continued on and performed many shows along the California coast.
Soon thereafter, Flea formed a "one-off" band with Kiedis, Slovak and Irons in 1983. The band, which was dubbed "Tony Flow and the Miraculously Majestic Masters of Mayhem" for its first gig, was a hit with the club audience. The band's name changed to the Red Hot Chili Peppers and the band quickly gained popularity around Los Angeles. Over the course of the next six months, the Red Hot Chili Peppers played many shows in Los Angeles clubs and became something of an underground hit. The band scored a record deal with EMI after just that short period of time and was set to record its first album. Unfortunately, What Is This? had also signed a record deal two weeks earlier. Since Slovak and Irons considered the Red Hot Chili Peppers to merely be a side project and not a serious commitment, they left the band to concentrate on What Is This?. With What Is This?, Irons recorded two EPs (Squeezed (1984), 3 Out of 5 Live (1985)) and one full length album (What Is This? (1985)). The band broke up following the recording of the self-titled What Is This? album as Slovak became frustrated with the band and rejoined the Red Hot Chili Peppers. In the meantime, Irons played on several tracks on an album by the duo Walk the Moon, made up of Johannes and Natasha Shneider. After hearing that drummer Cliff Martinez had resigned, Irons, who was out of work and finally separated from other commitments, returned to the Red Hot Chili Peppers in 1986.
Irons can be heard playing drums on the Red Hot Chili Peppers' first demo tape, as well as their third album, The Uplift Mofo Party Plan (1987). Contrary to popular belief he does not play on the band's cover of Jimi Hendrix's Fire first released in 1987 and more commonly known from its inclusion on The Abbey Road EP in 1988– this was recorded with Cliff Martinez on drums during the Freaky Styley sessions. When childhood friend and bandmate Hillel Slovak died of a heroin overdose on June 25, 1988, Irons left the Red Hot Chili Peppers. Irons stated that he did not want to be part of a group where his friends were dying. In 2006, Irons said Slovak's death had been such a huge shock that he had been suffering from depression ever since.
On August 12, 2012, Irons and Cliff Martinez again joined the Chili Peppers onstage at their show in Los Angeles for a performance of "Give it Away".
After Irons left the Red Hot Chili Peppers, he went to a psychiatric hospital to receive treatment. After a brief stint with Joe Strummer's backing band the Latino Rockabilly War, Irons teamed up with Johannes and Shneider in 1990 to form Eleven. With Eleven, Irons recorded the albums Awake in a Dream (1991) and Eleven (1993). Midway through the recording of Eleven's third album, Thunk (1995), Irons departed to drum with Pearl Jam, and Matt Cameron of Soundgarden played drums on the album's remaining four tracks. Irons returned to the band once again in 2002 prior to the recording of the band's fifth album, Howling Book (2003). Irons' Eleven bandmate Natasha Shneider died on July 2, 2008, following a battle with cancer. Prior to Shneider's death, the band was working on a sixth album due for release in the fall of 2008.
Irons was asked by bassist Jeff Ament and guitarist Stone Gossard to join Mookie Blaylock, the band that would become Pearl Jam, in 1990, when the band was first forming and still looking for a singer and a drummer. Although he did not join the band at that time because he was committed to his own band, Eleven, he did pass on a cassette of the band's work to a singer and local musician in San Diego named Eddie Vedder. Irons had formed a friendship with Vedder after meeting him through the Southern California music scene and would play basketball with him. Vedder subsequently joined the band. Irons also called the Red Hot Chili Peppers in 1991 and asked the band to allow Vedder's new group to open for the band on its forthcoming Blood Sugar Sex Magik tour. Irons became the official drummer for Pearl Jam in late 1994 following the firing of drummer Dave Abbruzzese. His first recording with the band was "Hey Foxymophandlemama, That's Me" for Vitalogy (1994). Gossard said, "Jack entered the band right at the end of making Vitalogy. Jack's a breath of fresh air, a family man. Everybody had a strong sense of friendship with him immediately. He was just there to play drums and help out." Irons made his debut with the band at Neil Young's 1994 Bridge School Benefit, but he was not officially announced as the band's new drummer until its 1995 Self-Pollution satellite radio broadcast, a four-and-a-half-hour-long pirate broadcast out of Seattle, Washington which was available to any radio stations that wanted to carry it. Irons joined the group and played Pearl Jam's live shows supporting the Vitalogy album.
Irons performed with other members of Pearl Jam on Neil Young's 1995 album, Mirror Ball, and subsequently toured Europe as part of Young's backing band. With Irons, the band recorded its fourth studio album, No Code, released in 1996, for which Irons also toured. The band subsequently released Yield in 1998. "Do the Evolution" (from Yield) received a Grammy nomination for Best Hard Rock Performance. As a member of Pearl Jam, Irons brought a unique drumming style to the band, particularly in the way he played his fills and with his use of a trash can lid as a cymbal. Irons co-wrote the music for the No Code songs "Who You Are", "In My Tree", "Red Mosquito", and "I'm Open". He also wrote and sang on the Pearl Jam songs "Happy When I'm Crying" (from the 1997 fan club Christmas single), "●" (from Yield), and "Whale Song" (from the 1999 Music for Our Mother Ocean Vol. 3 compilation). He played with Pearl Jam through March 20, 1998. In 1998, prior to Pearl Jam's U.S. Yield Tour, Irons left the band due to dissatisfaction with touring. Pearl Jam's sound engineer Brett Eliason stated, "We went and did Hawaii and Australia with Jack. When we came back, Jack wasn't in a position to carry on. He made that decision more or less by himself. He can be a really great drummer but he had difficulty on tour putting out the energy for the length of shows they were doing. I don't know if he thought they'd put things on hold for him." Vedder said, "I think that him deciding that he wasn't going to be in the band really hurt." Coincidentally, Matt Cameron, from Soundgarden, replaced him again as he did four years prior on Eleven's Thunk.
On September 7, 2004, Irons released a solo album called Attention Dimension. Irons started creating his first pieces of drum music in 1994, but it wasn't until fall 1999, about a year after he left Pearl Jam, that he seriously began recording himself for a possible solo album. The album features appearances by former bandmates such as Alain Johannes, Flea, Eddie Vedder, Stone Gossard, Jeff Ament, and Les Claypool. Vedder contributed vocals to a cover of Pink Floyd's "Shine on You Crazy Diamond". Johnny Loftus of Allmusic said, "Attention Dimension is the drummer's chance to be in the bright white klieg light."
Aside from the aforementioned bands, Irons recorded and toured as a member of Joe Strummer's backing band The Latino Rockabilly War for the album Earthquake Weather (1989), and also toured with Redd Kross in support of the band's album Third Eye (1990). He appears in Redd Kross' promotional video for the song "Annie's Gone". In 1992, Raging Slab (a band notorious for having over 25 different drummers over the course of the band's 18-year career), complete with Irons on drums, began recording the follow-up to its 1989 RCA Records self-titled debut, with producer Michael Beinhorn at the helm. The entire album was recorded, mixed, and mastered; however when RCA Records executives heard the album, it was rejected. The album, titled Freeburden, remains unreleased. In 2000, Irons played as part of the initial line-up of Colonel Les Claypool's Fearless Flying Frog Brigade. Irons is featured on the track "Milky Ave" on the album Ultra Payloaded (2007) by Perry Farrell's band Satellite Party. Joining him on the album is former bandmate Flea. Irons recorded for Spinnerette, which features Eleven bandmate Alain Johannes, contributing to the band's 2009 album, Spinnerette. Most recently, he played drums on Die Mannequin's album FINO + BLEED and he added studio drums to several tracks of Hole's latest release, Nobody's Daughter. In 2012 he appeared on former Chili Pepper bandmate, Flea's debut solo EP Helen Burns. Aside from popular music, Irons has worked as a drumming advisor and teacher for numerous U.S. television projects.