Traditional systemic therapies are frequently prescribed for the treatment of hidradenitis suppurativa (HS). Clinicians consider antibiotics, retinoids, antiandrogens, immunosuppressants, and less common treatment, such as fumarates, in the management of HS. Different classes of medications have been selected to treat HS based on their ability to target various pathways of the condition. Concerns about infection, such as infection with Clostridium difficile, necessitates switching therapy or shortening the course of therapy with specific antibiotics. This review explores the outcomes with the use of numerous medical therapies and postulates explanations for their efficacy or lack of response. Data on long-term safety and efficacy with traditional systemic therapies are lacking.