Hidradenitis suppurativa (HS) is a chronic inflammatory condition with substantial physical, psychosocial, and systemic burdens, including increased risk of comorbid metabolic, cardiovascular, and inflammatory conditions. Effective management requires a multimodal approach tailored to disease severity, comorbidities, and individual patient needs. This chapter explores non-antibiotic and non-biologic systemic therapies, focusing on hormonal modulators, metabolic therapies, oral retinoids, and non-biologic immunomodulators. These therapies address specific disease mechanisms and comorbidities but may require combination strategies for optimal efficacy and continued monitoring for therapy-related side effects. Recognizing the heterogeneous nature of HS, this chapter emphasizes a personalized approach integrating systemic treatments and lifestyle interventions to achieve long-term disease control and improved quality of life.