Osteoprotegerin (OPG) is supposed to participate in the development of atherosclerosis and cardio-cerebrovascular disease. However, the results of research on relationship between OPG and ischemic stroke (IS) are controversial. Therefore, we carried out the first systematic review and meta-analysis to evaluate prognostic effect of osteoprotegerin in patients with IS. We comprehensively searched databases of PubMed, Embase, and the Cochrane Library through 21 August 2023 to identify observational studies that evaluated effect of OPG on poor functional outcome (modified Rankin Scale mRS Score of 3-6) and mortality in patients with IS. Adjusted odds ratios (aOR) with a 95% confidence interval (CI) of each included study were used as much as possible to assess the pooled effect. Five studies that enrolled 4,506 patients in total fulfilled our inclusion criteria. Three studies were included in the pooled analysis for each endpoint since one of the included studies had provided data on poor functional outcome as well as mortality. OPG was neither associated with poor functional outcome (aOR 1.29, 95% CI 0.90-1.85) nor with mortality (aOR 1.57, 95% CI 0.90-2.74) in patients with IS. There is insufficient evidence to demonstrate the correlation between OPG and mortality or poor functional outcome in IS patients. OPG cannot be applied to predict worse neurological function in IS patients based on the current evidence.