In 2002, Tankian and Rage Against the Machine/Audioslave guitarist Tom Morello co-founded a non-profit political activist organization, Axis of Justice. During his musical career, he has released five albums with System of a Down, one with Arto Tunçboyacıyan (Serart), as well as his debut solo album Elect the Dead and a live orchestral version incorporating the Auckland Philharmonia Orchestra Elect the Dead Symphony. He is currently producing his second solo album, Imperfect Harmonies. Tankian also founded Serjical Strike Records, a label which promotes bands that may not otherwise be signed to a label.

Tankian was born in Beirut, Lebanon on August 21, 1967. His father is Khatchadour Tankian. When he was eight years old his family immigrated to Los Angeles, California. In his youth, he attended a school for Armenian-Americans, The Rose & Alex Pilibos School, which was also attended by Tankian's future System of a Down bandmates Daron Malakian and Shavo Odadjian. Doing well academically Tankian attended California State University. This is where Tankian first began to play instruments and write songs.[citation needed]

The early beginnings of System of a Down lie in a band named Soil (not to be confused with the Chicago-based band Soil) with Tankian on vocals, Malakian on guitar, and Odadjian acting as the band's manager at that time. The band soon changed their name to System of a Down, after a poem Malakian wrote called "Victims of a Down." The band later added drummer John Dolmayan, and Odadjian switched from manager to bass.[citation needed] The band quickly began touring the Southern California rock clubs, and began to attract a strong following.

During System of a Down's days, Tankian was the vocalist in other bands for certain songs such as "Mushroom Cult" by Dog Fashion Disco and lent his vocals to the song Mein by Deftones. He also sang backup vocals on a song for Hed PE called "Feel Good". He produced "Enter the Chicken" by Buckethead, and provided vocals to the Buckethead songs We Are One, Coma, and Waiting Hare. With Serjical Strike Records, he endeavors to offer those musicians often ignored by the mainstream a possibility to release their music and be heard. The first release of Tankian's new label was Serart, an album by Tankian himself, and Arto Tunçboyacıyan, a Turkish-Armenian friend of Tankian's.

In 2007, Serj composed and wrote "The Essence of Tequila" and "Chicakong" for the video game soundtrack of John Woo Presents Stranglehold. He also helped with "Stranglehold Rough 2" and "Pianoimprovstrangle 2".

More recently, he sang with Les Rita Mitsouko on the song "Terminal Beauty". Also, he sang with the band Fair to Midland during a live improvisational version of their song "Walls of Jericho", from the album Fables from a Mayfly: What I Tell You Three Times Is True, which was a massive hit with fans. He often collaborates as well with his close friend, director Diran Noubar on various projects, including the voice-over of Noubar's "Armenia, a Country Under Blockade". Noubar played some guitar on Tankian's Elect the Dead album on the track "Saving Us" and directed the music video for "Baby".

Tankian is also politically involved. Together with Tom Morello, he founded the organization Axis of Justice. Tankian is a New Zealand resident and has a secondary vacation dwelling there. There has been a misconception that he intends to stay in New Zealand until the Iraq War is over, but as stated in an interview, Tankian has no intention of doing so. He often speaks publicly against violence and injustice in the world. Tankian released a new song "Fears" in November 2008 exclusively in support of Amnesty International's Global Write-A-Thon

Tankian told The Pulse of Radio that the highlights of his last eight months on the road may soon be documented in a DVD featuring videos, live performances and behind-the-scenes footage.[citation needed]

On March 16, 2009, Serj performed with the Auckland Philharmonia Orchestra in New Zealand, an orchestral version of the album Elect the Dead. The live performance was captured in a CD/DVD titled Elect the Dead Symphony which was released om March 9, 2010.

Tankian is currently co-writing a musical with the American playwright Steven Sater. It is based on the Ancient Greek tragedy Prometheus Bound. He stated that eight songs have been completed and that there will be a record.