In 1981, Araya was approached by Kerry King, who asked Araya to join his band, Slayer. Araya accepted, using his earnings as a respiratory therapist to finance the band’s 1983 debut album Show No Mercy. Araya requested time off of work from his employer, the Brotman Medical Center, for Slayer’s first European tour in 1984 and was denied; “‘We need you to come in today.’ They’d call me at 5:00 in the morning and wake me, ‘Someone’s not coming in, we need you to come in to work.'” After a month of sporadic attendance, his employers threatened termination; Araya replied “Well, I guess I’m fired.” Along with King, Araya was one of the two original members to remain in Slayer for the entire length of the band’s career, from 1981 to 2019.

In 2006, Araya underwent gallbladder surgery, which disrupted The Unholy Alliance tour. Originally set to launch on June 6, the tour was postponed to June 13. Araya was also unable to finish the vocals for a song entitled “Final Six,” which was to be included on Slayer’s 2006 album Christ Illusion; later released on the special edition of the album. Araya brought his children on the tour stating “it’s kind of cool to expose them at such a young age. My first concert, I was, like, 17.” “We [Slayer] have been fortunate- fortunate enough to have lasted as long as we have because a lot of bands don’t last that long.”

On January 7, 2010, Slayer announced on its official website that back surgery had been scheduled for Araya and that the planned tour would be canceled through April of that year. The site assured fans, “Slayer camp working hard to reschedule dates for later this year.” Araya is known for his aggressive headbanging and began experiencing back problems while the band was on tour in Australia/New Zealand/Japan in October 2009. Araya had an Anterior cervical discectomy and fusion. “The surgeon opened up my throat from the front,” he explained. “Apparently it’s easier that way. They pushed my oesophagus over to one side and did the repair work. It seems to have done the trick but I can’t headbang anymore.”

On March 12, 2010, Metal Hammer magazine published an interview with Slayer’s Dave Lombardo about Araya’s recovery. The drummer stated, “He’s recovering extremely quickly and really well. He is just moving forward and doing all the treatments and post operation stuff that he has to go through. He’s doing good.” On May 20, 2010, Slayer confirmed that they would play two songs on TV for Jimmy Kimmel Live! As a result of his surgery, Araya has significantly tempered his once aggressive on-stage movement and headbanging; now remaining relatively still during performances. On June 3, 2011, Araya received the keys to the city of his birth, Viña del Mar, Chile.

In 2014, Araya made a cameo in the heavy metal horror film Hairmetal Shotgun Zombie Massacre: The Movie, directed by Joshua Allan Vargas.

In 2016, Araya further explained that the main reason Slayer used satanic imagery was to scare people, in particular, the “Hollywood people,” wanting to separate themselves from the androgynous Sunset Strip metal scene of the 1980s.

From May 2018 to November 2019, with the last show being in their hometown, Los Angeles, Slayer embarked on what they called their final world tour, and eventually dissolved.