Cytokine release syndrome (CRS) is a potentially life-threatening systemic inflammatory reaction associated with immunotherapies and other medications, yet its risk profile across marketed drugs remains poorly characterized. This study aims to evaluate the risk of drug-induced CRS using real-world data, thereby providing valuable insights for clinical medication safety assessment. We employed reporting odds ratios to assess the disproportionality in reports of drug-induced CRS from January 2004 to December 2024. Using univariate, least absolute shrinkage and selection operator, and multivariate regression analyses, we explored drugs associated with CRS, and the area under the curve was used to evaluate model performance. We collected a total of 13,499 reports. According to the Anatomical Therapeutic Chemical classification system, antineoplastic and immunomodulating agents were associated with the highest number of drug-related CRS cases (n = 12,759). Drug signal detection revealed that axicabtagene ciloleucel was linked to most CRS events (n = 3,389). Furthermore, among the top 50 drugs implicated in CRS, the prescribing information for 38 of them did not mention any association with CRS. Our findings demonstrate that antineoplastic and immunomodulating agents are the main drugs associated with CRS. A total of 18 drugs were identified as independent risk factors for drug-induced CRS. Alarmingly, most high-risk drugs lack relevant CRS warnings in their package leaflets. Clinicians should strengthen clinical monitoring for these medications, especially within one month after administration. Updated safety labeling and further relevant research are also required to ensure the safety of clinical medications.