Antibiotics remain a cornerstone in the management of dermatologic conditions such as acne and hidradenitis suppurativa, underscoring the need for responsible antibiotic stewardship. This article explores the “dark side” of antibiotics, highlighting their role in disrupting the gut microbiome, elevating risks for infections like Clostridium difficile, and increasing resistance in Cutibacterium acnes and other microbes. Emerging evidence also links antibiotic use to reduced vaccine efficacy and diminished responses to cancer immunotherapy. To mitigate these risks, dermatologists should prioritize narrow-spectrum antibiotics and incorporate combination topical therapies containing benzoyl peroxide (BPO), such as the triple-combination of clindamycin, adapalene, and BPO, to help curb antibiotic resistance. Prudent antibiotic use, combined with topical regimens utilizing BPO, optimizes treatment outcomes while minimizing systemic adverse effects and resistance. Ongoing education and research are essential to refine prescribing practices that balance therapeutic benefits with long-term patient and public health.