Background: Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia among adults, particularly in Western nations. The introduction of Bruton’s tyrosine kinase (BTK) inhibitors as a treatment of CLL, namely, ibrutinib, which is a first-generation BTK inhibitor, has significantly improved the treatment landscape for CLL. However, ibrutinib has been associated with an increased risk of atrial fibrillation (AF) and hypertension. Real-world studies that compare the cardiovascular safety of ibrutinib with bendamustine plus anti-CD20 monoclonal antibody are not widely available. Methods: A retrospective cohort analysis using the TriNetX platform identified two patient groups: one treated with ibrutinib and the other with bendamustine and an anti-CD20 antibody. Propensity score matching balanced their demographic and clinical characteristics. The outcomes evaluated included the all-cause mortality and new-onset AF/flutter, hypertension, heart failure, ventricular arrhythmias, and bleeding. Results: No significant difference was observed in the all-cause mortality between the two cohorts. However, ibrutinib was associated with a higher risk of AF/flutter (HR 1.89, 95% CI 1.36–2.62; p < 0.05) and hypertension (HR 1.22, 95% CI 1.01–1.47; p = 0.04). Other outcomes, such as heart failure, ventricular arrhythmias, and bleeding, were not different between the cohorts. Conclusions: Ibrutinib remains a valuable option for the treatment of CLL, but is associated with significant cardiovascular risks, leading to it being superseded by the newer generation of BTKis, which offer less cardiovascular toxicities. These results highlight the TriNetX platform’s reliability as a real-world data source for validating clinical trial findings and highlight the importance of incorporating cardio-oncology into treatment plans for CLL patients with significant comorbidities.