In an interview, James Hetfield commented on the song's lyrical meaning:
“ It was an attempt to get back to the H.P. Lovecraft mythos with "The Thing That Should Not Be", "Call of Ktulu".[sic] This was about the Hounds of Tindalos, which was another crazy mind **** about these wolves that hunt through their nightmares and the only way you can get away from them is stay with angles. You can't even escape through sleep.”
Some of the lyrics bear a striking resemblence to the lyrics of "Seek & Destroy", one of the fourth single from the band's debut album Kill 'Em All (specifically, the "All Nightmare Long" lyrics "You run, you hide/but will be found" is reminiscent of the "Seek & Destroy" lyrics "Don't try running away/'cause you're the one we will find").