Introduction: Ischemic thromboembolic stroke is a significant complication in patients with atrial fibrillation. Cancer will aggravate this event due to increased clot formation and thromboembolism processes but simultaneously propose high-risk bleeding for oral anticoagulation. Left Atrial Appendage Occlusion (LAAO) is an alternative strategy to prevent stroke events with promising efficacy features without the bleeding risk of anticoagulation. This systematic review and meta-analysis aimed to compare LAAO as a safety choice for ischemic stroke prevention in atrial fibrillation patients with and without cancer. Materials and methods: We conducted systematic literature searching from the database until August 2023. Studies were eligible if cohort studies performed LAAO in atrial fibrillation patients with and without cancer. A risk of bias assessment was performed using the Newcastle-Ottawa Scale (NOS). Results: Three studies met the criteria, comparing 318 patients with cancer and 544 without cancer. Among these, two were included in the meta-analysis. The pooled analysis showed no significant difference between the two groups in stroke incidence (Hazard Ratio (HR) 0.62; 95% CI 0.26−1.50; p= 0.93), bleeding episodes (HR 0.93; 95% CI 0.47−1.84; p= 0.45), and death (HR 1.34; 95% CI 0.87−2.07; p= 0.19) following the procedure. Regarding device-related complications, there was also no difference (HR: 1.3; 95% 0.81−2.08; p= 0.28). Conclusion: LAAO has safety features in atrial fibrillation patients with cancer and has no significant differences in outcome, such as stroke incidence, bleeding episodes, death, and device-related complications, compared with non-cancer patients.