Blythe joined Lamb of God in 1995. Before Lamb of God was successful, he had previously worked as a cook.
Blythe also has a side project band known as Halo of Locusts, who were founded around 2004. A full length release was planned, but has yet to be released. They contributed to For the Sick, the tribute album for Eyehategod, covering "Dixie Whiskey". In 2005, Blythe worked with the metalcore outfit A Life Once Lost on their album Hunter. He provided additional vocals on the track "Vulture" as well as helped in the vocal processing of the track. He later worked with them again in 2007 on "Iron Gag." He also appeared on the song "Skull and Bones"" by the band Overkill and "Adoration for None" on Gojira's album The Way of All Flesh. He was also featured on Shadows Fall song, King of Nothing, on their 2009 release, Retribution.
Blythe was featured in many of his peers' DVDs, such as Killswitch Engage's (Set This) World Ablaze and Machine Head's Elegies. Blythe was also featured in Metal: A Headbanger's Journey, Working Class Rock Star and Melissa Cross's The Zen of Screaming.
He appears as Luke in the movie The Graves (2009), written and directed by Brian Pulido.
On 5 January 2012, Blythe announced that he would be running for President of the United States via a blog entry entitled "I want to be The Big Cheese". His official campaign slogan was "Fuck the dumb shit. Let's get real here." Blythe did not appear on the ballot in any of the fifty states or the District of Colombia.