Toxic epidermal necrolysis (TEN) is a severe and potentially fatal skin reaction often associated with the use of multiple medications. Given the severity and potentially high fatality rate of TEN, identifying high-risk drugs is essential for improving clinical medication safety. The reporting odds ratio (ROR) was used to assess drug-related TEN reports in the FAERS database between Q1 2004 and Q3 2024. Univariate analysis, LASSO regression, and multivariate logistic regression were employed to explore the risk factors associated with drug-induced TEN. Bonferroni correction was applied for multiple comparisons. A total of 218 drugs were identified as being associated with TEN, including anticonvulsants (26/218), antibiotics (54/218), non-steroidal anti-inflammatory drugs (12/218), antineoplastic agents (3/218), and immunomodulatory drugs (8/218). Multivariate regression analysis revealed that the age group 37–66 years, as well as 26 specific drugs, including lamotrigine, phenytoin, carbamazepine, ciprofloxacin, sulfamethoxazole, and amoxicillin, might be risk factors factors for drug-induced TEN. These findings provide valuable insights to assist clinicians in early identification of drug-induced TEN, and offer a theoretical foundation for future drug safety evaluations and personalized treatment strategies.Constrained by the inherent limitations of disproportionality analysis, the current research findings on drugs related to TEN have a certain degree of uncertainty. Future research can utilize more advanced and rigorous research methods to earnestly explore the causal relationship between drugs and TEN.