Next-generation Bruton’s tyrosine kinase inhibitors (BTKis) such as acalabrutinib and zanubrutinib have improved treatment outcomes in B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM), while reducing off-target toxicities compared to ibrutinib. However, their comparative cardiovascular safety profiles remain poorly characterized. This study evaluates real-world cardiovascular and clinical outcomes between zanubrutinib and acalabrutinib using a large multi-center database. We conducted a retrospective cohort study using the TriNetX Research Network (October 2017–December 2024) including adult patients with CLL, MCL, WM, or small B-cell lymphoma treated with zanubrutinib or acalabrutinib. Patients with prior exposure to other BTKis were excluded. After 1:1 propensity score matching, 2887 patients were included in each cohort. We assessed one-year outcomes including new-onset atrial fibrillation/flutter, cerebral infarction, hypertension, and all-cause mortality using Cox proportional hazards modeling. The rate of AF/flutter events observed in the zanubrutinib group (4.05%) was numerically lower compared to the acalabrutinib group (5.25%). Time-to-event analysis did not demonstrate a statistically significant difference in AF risk over time (HR 0.777, 95% CI 0.597–1.012; p = 0.06), which was similar in binary analysis (OR 0.761, 95% CI 0.581–0.997; p = 0.05). Cerebral infarction rates were similar between groups (1.09% vs. 1.12%), with no significant difference in time-to-event analysis (HR 0.984, 95% CI 0.596–1.626; p = 0.95) or binary analysis (p = 0.91). There was no significant difference in onset of hypertension in the zanubrutinib cohort (HR 1.199, 95% CI 0.957–1.501; p = 0.11) All-cause mortality was not statistically significant between the two groups (HR 0.865, 95% CI 0.740–1.012; p = 0.07). In this large, real-world analysis, fewer AF/flutter events were observed with zanubrutinib at one year; however, time-to-event analysis did not demonstrate a statistically significant difference in AF risk over time. Notably, hypertension, cerebral infarction, and all-cause mortality occurred at similar rates. This suggests zanubrutinib and acalabrutinib share similar cardiovascular safety profiles overall. However these findings are hypothesis-generating and require prospective validation before definitive conclusions about cardiovascular risk can be drawn.