ABSTRACT Background Bruton’s tyrosine kinase inhibitors (BTKis) are targeted treatments for B-cell tumors but have significant side effects. This study assesses and contrasts the side effects of BTKis alone and its four combination therapies. Research design and methods The reporting odds ratio (ROR) was used to analyze the data on three BTKis monotherapies and combinations of ibrutinib with rituximab, obinutuzumab, venetoclax, and lenalidomide in the FDA Adverse Event Reporting System (FAERS) database up to December 2022. Results We analyzed the top 20 PTs for each treatment regimen. In monotherapies, atrial fibrillation (ROR (95% CI): 9.88 (9.47–10.32)) in zanubrutinib and rash (6.97 (5.42–8.98)) in acalabrutinib had higher associations. In combinations, infection (6.86 (6.11–7.70)), atrial fibrillation (27.96 (22.61–34.58)) and myelosuppression (10.09 (8.89–11.46)) were vital signals when ibrutinib was combined with obinutuzumab, and pyrexia (4.22 (2.57–6.93)) had a high signal value when combined with lenalidomide. Hemorrhage had a lower signal value when combined with venetoclax compared to ibrutinib alone (2.50 (2.18–2.87) vs 3.60 (3.52–3.68)). Conclusions The ibrutinib-obinutuzumab combo has the highest risk of infection, atrial fibrillation, and myelosuppression, and the ibrutinib-lenalidomide combo has the highest risk of pyrexia. However, the ibrutinib-venetoclax combo has a lower risk of hemorrhage than monotherapy.