Introduction Allopurinol is a known cause of severe skin reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis. The aim of this study was to characterize the clinical presentation, identify risk factors, and evaluate the best treatment strategies for severe skin reactions due to allopurinol. Method A systematic search was conducted in the PubMed, Embase, and Scopus databases to identify English case reports and case series of allopurinol-induced Stevens‒Johnson syndrome and toxic epidermal necrolysis. Other study types were excluded. The quality of the included studies was assessed via the Joanna Briggs Institute (JBI) critical appraisal checklists. The study was supported by the research council of Alborz University of Medical Sciences. Results In total, 928 articles were identified through a database search. Finally, 68 articles including 91 patients (48 males and 43 females) were included in the analysis. The reaction occurred after a median of 16 days (8.5 days in those with prior reactions to allopurinol). Rapid dose escalation was observed in half of the patients. Mucosal involvement was observed in 72 (90.0%) patients. Corticosteroids, IVIG, cyclosporine, and plasma exchange were the most common treatment modalities. Twenty-one patients (23.6%) died, and 68 (76.4%) were discharged. Conclusion Although the prevalence of gout is 2–3 times greater in men than in women, the number of cases was approximately equal in both sexes, which may be related to the higher rate of reports in women. Rapid dose escalation is a risk factor for the occurrence of severe skin reactions. Corticosteroids, IVIG, and plasma exchange appear to be reasonable treatment options.