Helstrom was based on the Marvel Comics characters Daimon and Satana Hellstrom, but in the series they were renamed Daimon and Ana Helstrom.

The series was originally planned as the first installment in Marvel Television's 'Adventure into Fear' franchise, a horror-themed corner of the Marvel Cinematic Universe that would not cross over with the MCU films or other Marvel Television series; further development of the franchise was cancelled when Marvel Television was shut down in December 2019.

Hulu and Marvel originally announced Helstrom alongside a planned Ghost Rider series in May 2019, intending them to be interconnected similarly to Marvel's Netflix series, but Hulu dropped the Ghost Rider project by the end of September 2019.

The series filmed in Vancouver under the working title 'Omens' from October 7, 2019 to March 14, 2020.

In April 2020, Marvel terminated showrunner Paul Zbyszewski's overall deal, partly due to the COVID-19 pandemic, though he continued to work on post-production for the series.

By July 2020, Disney dropped 'Marvel's' from the official title, renaming it simply Helstrom to distance the Marvel brand from the show's horror content and avoid viewers expecting an MCU-film-like tone. The Marvel logo was also omitted from the start of each episode, unlike other Marvel Television series.

The Roxxon Corporation, a company that appears throughout the MCU, is referenced in the series, representing one of the few explicit ties to the wider Marvel Cinematic Universe.

Helstrom became the final live-action series produced under the Marvel Television banner, being cancelled by Hulu on December 14, 2020 after Marvel Television had already been absorbed back into Marvel Studios.

Critics such as Josh Bell of Comic Book Resources noted that the series barely resembled a superhero story and was comparable to a mid-level CW supernatural drama, while praising Sydney Lemmon's portrayal of Ana Helstrom as the most prominent LGBTQ character in any Marvel TV series to date.