The management of warfarin therapy presents clinical challenges due to its narrow therapeutic index. We aimed to evaluate the comparative effectiveness of different management strategies in patients using warfarin. PubMed, Embase, Cochrane CENTRAL, CINAHL, and EBSCO Open Dissertation were searched from inception to 8 May 2024. Randomized controlled trials that compared the following interventions: patient self-management (PSM), patient self-testing (PST), anticoagulation management services (AMS), and usual care in patients prescribed warfarin for any indication were included. Risk ratios (RR) with 95% confidence interval (CI) were estimated using a random-effects model. Surface under the cumulative ranking curves (SUCRA) were used to rank different interventions. The certainty of evidence was assessed using the Confidence in Network Meta-Analysis (CINeMA) online platform. This study is registered with PROSPERO (CRD42023491978). Twenty-eight trials involving 8100 participants were included, with follow-up periods of 1-24 months. Mean warfarin dosages were 4.9-7.2mg/day. Only PSM showed a significant reduction of major TE risk compared with usual care (RR=0.41; 95% CI: 0.24, 0.71; I2=0.0%) with moderate certainty of evidence. The 97.6% SUCRA also supported the beneficial effects of PSM over other interventions. The combined direct and indirect evidence showed significantly higher TTR in PSM compared with usual care (MD=7.39; 95% CI: 2.39, 12.39), with very low certainty. However, direct evidence showed non-significant TTR improvement (MD=6.49; 95% CI:-3.09, 16.07, I2=96.1%). No differences across various strategies were observed in all-cause mortality, major bleeding, stroke, transient ischemic attack, and hospitalization. PSM reduces the risk of major TE events compared with usual care, tends to improve anticoagulation control, and should be considered where appropriate. Agency for Healthcare Research and Quality (grant ID 5R18HS027960).