Kilgariff and Hardstark each select a single murder, true crime story, survivor story, or historical event to recount and discuss. The podcast consists mainly of dialogue between the hosts with one host telling the story and the other host reacting and providing commentary. Episodes were initially thematically based, though this concept was abandoned early in the series. Episodes 1-32 were titled with murder-themed puns and pop culture references. From then on, episode titles were based on jokes from the conversations within the episodes. While the show traditionally consists only of Kilgariff, Hardstark and producer Steven Ray Morris, a few episodes have featured guest appearances. Past guests have included Guy Branum, Paul Holes, Patton Oswalt, Bellamy Young, Conan O'Brien, and Cameron Britton, among others. Additionally, My Favorite Murder has collaborated with other podcasts, including the Cracked podcast, Unqualified with Anna Faris, The Dollop, Harmontown, Disgraceland and Movie Crush. Karen Kilgariff was also on Mother, May I Sleep With Podcast in an episode on the movie Flowers in the Attic.
Full episodes are released weekly on Thursdays, ranging in length from 60 to 120 minutes. "Minisodes" are released Mondays, and are typically 30–45 minutes long. Minisodes initially focused solely on "Hometown Murders," which include listeners' personal connections or experiences with crime submitted via email. Minisodes have since expanded also to include topics such as the paranormal, hidden objects, family secrets, first responder stories, or whatever topics the hosts have personally requested for.[16]
Kilgariff and Hardstark have both referred to the podcast as a sort of therapy to deal with their own anxieties about true crime.[17] They often discuss common problematic themes in true crime, such as mental illness, sex work, sexual abuse, religion, women's rights, and victim's rights. Within the discussion of the crimes, they also discuss personal experiences and anecdotes. These topics often include previous substance abuse, Irish Catholicism, Judaism, sobriety, therapy/mental health, epilepsy, stand-up comedy, and growing up in California.
Each episode ends with the hosts saying their catchphrase "Stay Sexy and Don't Get Murdered." Hardstark then asks her siamese cat Elvis: "Elvis, do you want a cookie?" and he meows into the microphone as the episode ends. After their move to the Exactly Right offices, Hardstark recorded Elvis on her phone at home, and it was then added to the end of the podcast in post-production. Elvis died in December 2020, though his recording is still played after each episode.[18]
