The show takes a myth-busting approach to controversial topics and current events, with fact checking and research of the scientific literature, as well as interviewing relevant experts.

Episode topics have included immigration, gun control, ghosts, climate change, acne, and antidepressants, among others.

[7][10][11] Zukerman has said that the idea for Science Vs came from news headlines about Gwyneth Paltrow wanting women to participate in a "health practice" of vaginal steaming, which she thought could combine science with humor.

[13] In February 2022 Zukerman announced that in response to COVID-19 misinformation[broken anchor] spread by The Joe Rogan Experience, another Spotify podcast, Science Vs would suspend regular programming and air only shows that fact-check other Spotify podcasts.

Zukerman called the platform's support of Rogan's COVID-19 misinformation "a slap in the face" in an email to Spotify CEO Daniel Ek.