Between 2004 to 2005, the group recorded the follow up to Steal This Album!, a double album, which they released as separate installments six months apart from each other, notably including album cover artwork by Malakian's father, Vartan Malakian, which was designed to connect the two separate album covers. The first album, Mezmerize, was released on May 17, 2005 to favorable reviews by critics. It debuted at #1 in the United States, Canada, Australia and all around the world, making it System of A Down's second #1 album. First week sales rocketed to over 800,000 copies worldwide. The Grammy Award-winning single "B.Y.O.B.", which questions the integrity of military recruiting in America, worked its way up the Billboard Modern Rock and Mainstream Rock charts. The next single, "Question!" was released with Shavo Odadjian co-directing the music video. Following the release of Mezmerize, the band toured extensively throughout the United States and Canada with The Mars Volta and Bad Acid Trip supporting.
The second part of the double album, Hypnotize, was released on November 22, 2005. Like Mezmerize, it debuted at #1 in the US, making System of a Down, along with The Beatles, Guns 'N Roses, and rappers 2Pac and DMX, the only artists to ever have two studio albums debut at #1 in the same year. In February 2006, System of a Down won the Grammy for Best Hard Rock Performance for "B.Y.O.B.", beating out other established artists such as Nine Inch Nails and Robert Plant. Their second single off the Hypnotize album, "Lonely Day" was released in March in the United States. System of a Down released "Kill Rock 'N Roll" and "Vicinity of Obscenity" as their next promo singles. The band headlined Ozzfest 2006 in cities where tour founder Ozzy Osbourne opted not to appear or wasn't playing on the main stage.
Whereas on System of a Down's previous albums most of the lyrics were written and sung by Tankian and the music was co-written by Tankian and Malakian (and sometimes Odadjian) much of the music and lyrics on Mezmerize/Hypnotize were written by Malakian who also took on a much more dominant role as vocalist on both albums, often leaving Tankian providing keyboards and backing vocals.
Concert footage and interviews with the band concerning the importance of helping create awareness and recognition of the Armenian Genocide were featured in the 2006 film Screamers, directed by Carla Garapedian. An interview with Tankian's grandfather, a survivor of the Genocide, was also included in the film as well as Tankian's and Dolmayan's meeting with (then) Speaker of the House Dennis Hastert during which the two musicians campaigned for the United States government's official recognition of the Genocide. Footage of Tankian and Dolmayan marching with protesters outside of the Turkish embassy in Washington D.C. was also used in Screamers.
System of a Down was honored at a University of Southern California game at the Los Angeles Coliseum in Los Angeles, California in 2006. The Trojan Marching Band, along with Dolmayan and Odadjian, performed three System of a Down songs: "Toxicity," "Sugar," and "Hypnotize." System of a Down's song "Lonely Day" was nominated for Best Hard Rock Performance in the 49th Grammy Awards in 2007, but lost to "Woman" by Wolfmother.