Non-steroidal anti-inflammatory drugs (NSAIDs) are available as over-the-counter drugs, and they are commonly used in children for their antipyretic, analgesic, and anti-inflammatory effects. NSAIDs are among the most frequently reported drugs associated with hypersensitivity reactions and even with anaphylaxis. A complete evaluation of the patients based on reported clinical manifestations, timing of the reaction, the presence of underlying disease, and reactions to other NSAIDs allows clinicians to stratify children with a history of reaction to NSAIDs. Although NSAID-induced hypersensitivity reactions have mainly been investigated in adults, recent studies have aimed to explore their epidemiology in the pediatric population. This review will cover the current understanding of clinical manifestations, the risk factors, and the different phenotypes of NSAID-induced hypersensitivity reactions with a comprehensive overview of the epidemiologic data from past to present and the practical approach to the management of NSAID hypersensitivity in children and adolescents.