Aim: The effectiveness and safety of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) patients with stage III chronic kidney disease (CKD) are still subject to debate. We therefore assessed and compared the effectiveness and safety of DOACs vs. warfarin in this population. Methods: A cohort of patients with an inpatient or outpatient code for AF and stage III CKD who were newly prescribed an oral anticoagulant (OAC) was created using administrative databases from the Quebec province of Canada between 2013 and 2017. The primary effectiveness outcome was a composite of ischemic stroke, systemic embolism, and death, whereas the primary safety outcome was a composite of major bleeding within a year of DOAC vs. warfarin initiation. Treatment groups were compared in an on-treatment analysis using inverse probability of treatment weighting and Cox proportional hazards. Results. A total of 8,899 included patients filled a new OAC claim: 3,335 for warfarin and 5,564 DOACs. Compared with warfarin, rivaroxaban 15 mg and 20 mg presented a similar effectiveness and safety composite risk. Apixaban 5.0 mg was associated with a lower effectiveness composite risk (Hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.65–0.88) and a similar safety risk (HR 0.94; 95% CI 0.66–1.35), whereas apixaban 2.5 mg was associated with a similar effectiveness composite (HR 1.00; 95% CI 0.79–1.26) and a lower safety risk (HR 0.65; 95% CI 0.43–0.99). Conclusion: In comparison with warfarin, rivaroxaban and apixaban appear to be effective and safe in AF patients with stage III CKD.