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Background: Non-valvular atrial fibrillation (NVAF) poses risks of mortality and thromboembolic events, necessitating anticoagulant therapy. Direct oral anticoagulants (DOACs) such as apixaban and dabigatran have emerged as alternatives to warfarin due to their convenience. Choosing the appropriate DOAC involves weighing benefits against risks, considering patient factors and preferences. Methods: A systematic review of observational studies directly comparing the effectiveness and safety of apixaban with other DOACs for NVAF was conducted. Cohort studies totaling 2,936,126 participants were analyzed, with meta-analysis conducted on 27 studies (N=2,135,415) reporting total event numbers. Primary outcomes including total mortality, major bleeding and thromboembolic events, were analyzed and compared across DOACs. Results: Apixaban had lower risks of major bleeding compared to dabigatran and rivaroxaban, while demonstrating similar efficacy in preventing stroke and systemic embolism. Apixaban was associated with a reduced risk of total mortality, ischemic stroke, and intracranial hemorrhage compared to rivaroxaban. Apixaban and dabigatran exhibited similar risks of death and intracranial hemorrhage, but apixaban showed superiority in preventing systemic embolism or stroke when compared to dabigatran. Conclusions: Observational evidence consistently favours apixaban over rivaroxaban, dabigatran, and edoxaban as the preferred first choice DOAC for NVAF patients accepting twice-daily dosing. Given its efficacy and safety profile, particularly in reducing major bleeding, apixaban is a suitable option for long-term anticoagulation in NVAF patients, supported by the recent availability of cost saving generic formulations.