Previously, Twiztid had performed mainly rap with only certain rock elements thrown in (such as horrorcore); however, on Unlikely Prescription, they ventured into a purely rock-oriented direction.

[8] In 2020, Twiztid had released two albums in the same year, April's Mad Season and November's Revelashen.

Rock music had appeared before on Twiztid's albums, but only as a supplement to the mainly-rap tracks (such as 2000's Freek Show and 2005's Mutant (Vol.

[10] Twiztid was influenced by various rock and metal artists, such as Rob Zombie, Godsmack, Linkin Park, among others.

Spencer Charnas (Ice Nine Kills), Dani Filth (Cradle of Filth), Rich Ward (Fozzy), and Matt Brandyberry (From Ashes to New) were all featured guests on the album, and their respective songs were released as digital singles prior to the album's release.