Objective: The objective of this systematic review and meta-analysis is to evaluate the efficacy, safety, time to international normalized ratio (INR) reversal, and total volume of four-factor prothrombin complex concentrate (4-PCC) administered using fixed-dose versus weight-based dosing strategies in patients requiring urgent warfarin reversal, with specific focus on clinical outcomes of hemostatic efficacy, thromboembolic events, and mortality rates. Methods: A comprehensive systematic review was conducted using the PubMed, Embase, and Cochrane databases from inception through October 2023. We searched for randomized clinical trials or observational studies that compared efficacy or safety outcomes of fixed versus variable 4-PCC dose in adult patients. Results: In the 14 included studies, the overall use of fixed-dose 4-PCC was associated with a lower likelihood of reaching the INR goal (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.80–0.89) compared to the variable-dose group. In addition, a significantly larger proportion of patients (169 of 651, 26%) required an additional dose of 4-PCC. The rates of mortality (RR, 0.85; 95% CI, 0.70–1.03) and thromboembolic events (RR, 1.27; 95% CI, 0.65–2.45) were similar between the two treatment groups. Conclusion This systematic review and meta-analysis showed that variable dosing of 4-PCC more successfully achieves the target INR for warfarin reversal compared to fixed dosing. However, the dosing strategies have similar mortality and thromboembolic rates. While fixed dosing offers a simpler approach, it may require additional administration. Future studies should focus on optimizing dosing strategies to balance efficacy, safety, and practicality in various clinical scenarios