Vitiligo, an autoimmune disorder causing depigmented skin patches, includes two types, segmental (SV) and non-segmental (NSV). Previously, NSV was off-label treated using Calcineurine inhibitors (Tacrolimus and Pimecrolimus). In 2022, the FDA approved Ruxolitinib cream, targeting the JAK/STAT pathway for NSV treatment based on promising results. This research conducts a retrospective descriptive safety assessment of Tacrolimus, Pimecrolimus, and Ruxolitinib safety in vitiligo treatment, utilizing the FDA Adverse Event Reporting System (FAERS) database spanning the period from 2013 to 2023 and including patients aged 2 years and above, encompassing both brand and generic names. A total of 844 adverse event reports involving 388 patients were extracted and categorized into dermatological and systemic groups for analysis. Tacrolimus resulted in 12 hospitalizations, two life-threatening events, and four disabilities. Pimecrolimus exhibited urticaria and pigmentation disorders, with tooth fracture as the primary systemic event. Pericarditis was the predominant systemic side effect of Ruxolitinib, followed by anemia, headache, and urosepsis. Local dermatological side effects reported were generally mild, not warranting treatment cessation. In conclusion, vitiligo significantly impacts patients’ psychological well-being, necessitating continuous post-marketing safety monitoring for topical medications.