Resistance of Cutibacterium acnes to topical antibiotics historically used to treat acne (topical erythromycin and clindamycin and, more recently, topical azithromycin and clarithromycin) has been steadily increasing and new topical antibiotics are needed. Minocycline is a semisynthetic tetracycline-derived antibiotic currently used systemically to treat a wide range of infections caused by Gram-negative and Gram-positive bacteria. In addition to its antibiotic activity, minocycline possesses anti-inflammatory properties, such as the downregulation of proinflammatory cytokine production, suppression of neutrophil chemotaxis, activation of superoxide dismutase, and inhibition of phagocytosis, among others. These characteristics make minocycline a valuable agent for treatment of dermatological diseases such as acne vulgaris and papulopustular rosacea. However, more frequent or serious adverse effects have been observed upon the systemic administration of minocycline than with other tetracyclines. Examples of serious adverse effects include hypersensitivity syndrome reaction, drug-induced lupus, idiopathic intracranial hypertension, and other autoimmune syndromes that may cause death. Here, we review adverse effects and drug–drug interactions observed with oral administration of minocycline and contrast this with topical minocycline formulations recently approved or under development for effectively treating dermatological disorders with fewer adverse effects and less drug interaction.