Minocycline is a medication commonly used for the treatment of acne vulgaris. The central nervous system-induced side effects of minocycline include headaches, pseudotumor cerebri, ataxia, and vestibular dysfunction. Many minocycline-related side effects have been presented in the literature, however, reports of depersonalization symptoms induced by the medication are rare. We present the case of a 37-year-old female diagnosed with perioral dermatitis treated with minocycline, who within 1 week suffered from severe depersonalization symptoms. The pathophysiologic mechanism of depersonalization induced by minocycline is unclear but various hypotheses include hypersensitivity of the serotonin system, drug-related metabolic encephalopathy, substance-induced temporal disintegration, and panic-disorder-related etiology. Depersonalization is a potentially severe and important side effect of minocycline that should be documented, further investigated, and recognized by clinicians.