Palko describes Depart from Me as being "an exorcism of sorts", stating that it is more personal than previous albums. Palko states that the album's lyrics do not focus on social commentary, but instead deal with life and "things that people can relate to". The album continues from the lyrical direction of Hell's Winter and distancing himself from the persona featured on Movies for the Blind. Palko felt that since becoming a father, he no longer wished to write the same type of lyrical content as he had in the past. Palko stated that "if people can't understand that, that's good, because I don't want to make music for assholes." While Hell's Winter deals with personal change, Depart from Me deals with the difficulty of implementing these changes.
Describing the recording process, Palko remembers that El-P had been working on a track, and Palko soon thought of a hook that would fit the song, and recorded its freestyle lyrics on the couch. El-P and Palko later decided not to record a studio take of the track "because it just had a vibe to it. I was out of my mind. I might as well have been a blind man being walked in front of a microphone. I was just out of it."
According to Palko, the music of Depart from Me does not rely on sampling, and instead features a guitar and synthesizer-oriented sound. Palko describes the album as incorporating pop influences while keeping an "indie sensibility". Palko states that he wanted to produce music that would appeal to a larger audience. Describing the album as rap rock, Palko states that he did not intend to produce an album that would replicate early fusion attempts, or more recent, popular acts within the genre, but to incorporate elements of more diverse influences. According to Palko:
"Friends of mine who make music [would say,] 'Listen to this group. It’s awesome' and instead of taking something from the music and being inspired by it, instead in hip-hop it’s 'I’m sample this.' Plagiarize and take the lyrics. [...] We were just fusing weird things that hadn’t been done before, so the blueprint to everything was to do what no one else was doing. I had no idea if any of it was going to work. In the beginning, I was terrified to release the music and then that ended up being, if I’m not terrified or at least somewhat scared to release [it], then I didn’t take any risk."
Palko describes the album's title track as being similar to Nine Inch Nails because guitarist Sean Martin had been listening to the band heavily during the production of the album.