Abstract Aims Bruton’s tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib, and zanubrutinib may have certain mechanisms of action (MOAs) related to adverse effects (AEs) on the cardiovascular system. We aimed to evaluate the cardiac AEs of BTKIs reported to the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and to compare the differences in cardiovascular toxicity of ibrutinib, acalabrutinib, and zanubrutinib. Methods Only primary suspect drugs from the FAERS database were extracted from January 2013 to December 2022 across all indications of FDA-approved BTKIs. Disproportionality was measured by reporting odds ratios (RORs) and information components (ICs). An additional disproportionality analysis was also performed from January 2020 to December 2022. Results A total of 10,353 cases involving ibrutinib, acalabrutinib and zanubrutinib were included. Ibrutinib was significantly associated with the incidence of cerebrovascular accidents, myocardial infarction and other thrombotic events. Acalabrutinib was associated with new signals, including cardiac failure, ventricular extrasystoles, pulmonary edema and angina pectoris, and hypertension and myocardial infarction were found in additional analyses. Furthermore, acalabrutinib was characterized by a much earlier onset of cardiovascular events. Only atrial fibrillation was associated with zanubrutinib use. Acalabrutinib and zanubrutinib had lower ROR values for cardiac AEs, and fewer signals for these two drugs compared with ibrutinib. Conclusion This study indicated that new AEs were not clearly noted on the label for acalabrutinib. It is suggested that the cardiovascular risks of BTKIs remain a concern and worth attention as next-generation BTKIs are discovered and developed.