Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome represents a rare yet grave consequence of medication usage, among which mefenamic acid, a widely utilized nonsteroidal anti-inflammatory drug (NSAID), stands as a notable culprit. This review carefully examines the complex relationship between mefenamic acid and DRESS disease, exploring the subtleties of its epidemiology, underlying pathophysiological mechanisms, diverse clinical manifestations, diagnostic challenges, therapeutic modalities, prognostic implications, and preventive strategies. This article aims to strengthen medical community awareness, identification, and effective therapy of mefenamic acid-induced DRESS syndrome by combining current knowledge with emerging research initiatives. © 2025 Elsevier B.V., All rights reserved.