Introduction <p>Chronic lymphocytic leukemia (CLL) is a B-cell malignancy that has been considered a separate clinical entity since the early twentieth century. However, in the past decades, it has been integrated with small lymphocytic leukemia (SLL) and considered different manifestations of the same disease. This review, therefore, aims to determine the efficacy and safety of zanubrutinib in treating CLL/SLL.</p> Methods <p>PubMed, CENTRAL, and ScienceDirect databases were comprehensively searched for records published until May 2024. Studies evaluating zanubrutinib as an intervention in managing CLL/SLL and published in English were included in the review. The results were pooled using Comprehensive Meta-Analysis (CMA) version 3 and Review Manager (RevMan) 5.4 statistical software and presented using forest plots.</p> Results <p>Our comprehensive online search yielded 666 articles, of which only five were included in the analysis after assessment based on eligibility criteria. A pooled analysis of the results showed that the progression-free survival (PFS) was significantly increased in patients who received zanubrutinib compared to controls (HR 0.467; 95% CI [0.33, 0.63] <i>p</i> &lt; 0.000001). However, the overall survival (OS) was comparable between both cohorts of patients (HR 0.80; 95% CI [0.58, 1.09] <i>p</i> = 0.16). Furthermore, the analysis showed that the overall response rate of CLL/SLL patients to zanubrutinib was (86.9%; 95% CI [83.6%, 90.3%] <i>p</i> = 0.05) and grade ≥ adverse events (AEs) occurred in about (62.5%; 95% CI [58.0%, 66.7%] <i>p</i> &lt; 0.05) of the patients.</p> Conclusion <p>The findings of our study indicate that zanubrutinib is more effective than other treatment modalities in preventing disease progression in CLL/SLL patients. However, it is comparable in its efficacy in preventing death in CLL/SLL patients. Therefore, further phase III clinical trials are required to establish the comparative efficacy of zanubrutinib in managing CLL/SLL patients.</p>