Aims: The aim of the present meta-analysis was to evaluate the effectiveness and safety of non–vitamin K antagonist oral anticoagulants (NOACs) vs. vitamin K antagonists (VKAs) in atrial fibrillation (AF) patients with polypharmacy. Methods and results: Randomized controlled trials or observational studies reporting the data about the NOACs and VKAs therapy among AF patients with polypharmacy were included. The search was performed in the PubMed and Embase databases up to November 2022. There were no differences in the rates of SSE but increased risk of all-cause death and major bleeding between moderate polypharmacy and severe polypharmacy versus no-polypharmacy patients. The use of NOACs compared with VKAs was significantly associated with reduced risks of stroke or systemic embolism (SSE) in AF patients with moderate polypharmacy (hazard ratios [HRs], 0.77 [95% confidence intervals [CIs], 0.69–0.86]) and severe polypharmacy (HR, 0.76 [95% CI, 0.69–0.82]) and there was no significant difference in major bleeding (moderate polypharmacy: HR, 0.87 [95% CI, 0.74–1.01]; severe polypharmacy: HR, 0.91 [95% CI, 0.79–1.06]) between the two groups. There were no differences in the rates of ischemic stroke, all-cause death, and gastrointestinal bleeding but reduced risk of any bleeding between the NOACs and VKAs users. Compared with VKAs, the risk of intracranial hemorrhage was reduced in patients with moderate polypharmacy but not in patients with severe polypharmacy in NOACs users. Conclusion: In patients with AF and polypharmacy, NOACs showed advantages over VKAs in SSE and bleeding, and non-inferiority in major bleeding, ischemic stroke, all-cause death, intracranial hemorrhage, and gastrointestinal bleeding.