Manglobe approached director Shūkō Murase with only a bare-bones concept: the title, a plot outline for episodes 1–3, and a design concept for Romdeau, leaving him free to develop the story toward a more existentialist direction.

Chief writer Dai Satō said he chose the title 'Ergo Proxy' simply because 'it sounds cool', while director Murase explained that René Descartes' phrase 'cogito, ergo sum' inspired the concept of two personalities existing within one person.

The writers initially did not intend to explicitly incorporate Gnosticism into the anime, but realized their personal beliefs reflected Gnostic ideas so well that they decided to use them deliberately.

Vincent Law was originally planned to be the sole lead protagonist with Re-l as a supporting character, but as her character was fleshed out she became so strong that the writers split the narrative between the two of them.

The anime's main theme is Radiohead's 'Paranoid Android', used as the ending theme in the original Japanese broadcast, while the opening theme is 'Kiri' by Monoral; later streaming releases replaced 'Paranoid Android' with Yoshihiro Ike's 'Fellow Citizens'.

Many characters are named after real philosophers and thinkers, including Derrida, Lacan, Husserl, Berkeley, Kristeva, Deleuze and Guattari, reflecting the show's heavy philosophical influences.

The character name Re-l (124C41+) references 'Ralph 124C41+', a science fiction novel by Hugo Gernsback, and the name Daedalus references the Greek mythological father of Icarus.

Ergo Proxy was the first WOWOW anime production to be broadcast in 5.1 channel surround sound.

IGN ranked the show's opening sequence as the 10th greatest anime opening, comparing its dark visuals paired with an optimistic theme song to a Nine Inch Nails music video.

On June 12, 2015, China's Ministry of Culture listed Ergo Proxy among 38 anime and manga titles banned in the country.