Vaccine-associated erythema multiforme (EM) remains under-researched, impacting global vaccine safety evaluations. This study examines the global and regional burden of EM and its association with specific vaccines to optimize vaccination strategies. We analyzed data from the WHO pharmacovigilance database on vaccine-associated EM from 1967 to 2023 (n=131,255,418 reports). Reporting frequencies, reported odds ratios (ROR), and information components (IC) were calculated for 16 vaccines across 170 countries. We identified 6,355 cases (males, n=3,182 [50.07%]) of vaccine-associated EM from a total of 46,378 reports of all-cause EM. While vaccine-associated EM has been consistently reported, there has been a notable increase in reported incidence particularly in 2010 and 2020. Measles, mumps, and rubella vaccines had the highest association with vaccine-associated EM reports (ROR, 8.75 [95% confidence interval (CI), 8.11-9.44]; IC, 3.10 [IC0.25, 2.97]), followed by hepatitis B (8.54 [7.66-9.51]; 3.06 [2.88]), hepatitis A (8.11 [7.01-9.39]; 2.98 [2.74]), typhoid (6.50 [4.75-8.90]; 2.60 [2.07]), encephalitis (5.86 [4.35-7.91]; 2.47 [1.96]), diphtheria, tetanus toxoids, pertussis, polio, and Hemophilus influenza type b (5.70 [5.42-5.99]; 2.46 [2.38]), pneumococcal (5.56 [5.11-6.06]; 2.45 [2.31]), rotavirus (4.96 [4.21-5.84]; 2.29 [2.01]), varicella-zoster (4.44 [3.99-4.95]; 2.13 [1.95]).Vaccine-associated EM reports were more strongly correlated with younger age groups and males. The overall fatality rate of vaccine-associated EM was 0.04%. The rise in vaccine-associated EM across multiple vaccines, especially in younger populations, highlights the need for closer monitoring and more informed vaccination practices to mitigate adverse reactions.