Abstract Background The worldwide development of immune system targeting/anticancer drugs has revolutionized immuno‐oncology, but their implication in thrombotic microangiopathy syndromes (TMA) is increasingly suspected. Using real‐world data, the aim of this study was to identify drugs associated with TMA reporting and to describe the evolution of TMA reporting over time with a focus on these drugs. Methods A global disproportionality study was performed using the individual case safety reports (ICSRs) extracted from the World Health Organization (WHO) pharmacovigilance database (VigiBase) from its inception (1968) to April 30, 2022. Results Of the 31,251,040 ICSRs, 6946 cases of suspected drug‐induced TMA were included from 55 countries. The outcome was fatal in 18.2% of cases. A total of 72 immune system targeting/anticancer drugs were associated with significant overreporting, including 17 drugs with a potential new safety concern for TMA. Although the rate of TMA reporting per million of ICSRs has remained fairly stable, an absolute increase in reported cases of suspected drug‐induced TMA has been observed over the last decade. The pattern of drugs reported in TMA has evolved with a substantial increase in the proportion of cases involving immune system‐targeting drugs/anticancer drugs from 47.3% (205/433) in the period 1992–2001 to 80.7% (3819/4730) in the period 2012–2021. Conclusion Several recently marketed immune system targeting/anticancer drugs have been identified as potential new drugs associated with TMA, which will require confirmatory studies. The number of drugs associated with TMA reporting markedly increased within the past 10 years, primarily due to innovative anticancer drugs.