Background: Risk stratification of patients for incidence of stroke and its outcomes can aid in decision-making regarding treatment options and rehabilitative care. We systematically reviewed the literature to provide comprehensive evidence for the value of serum soluble suppression of tumorigenicity-2 (sST-2) in the prediction of stroke incidence and the evaluation of post-stroke outcomes. Methods: The Medline, Scopus, Web of Science, and Embase databases were searched until the end of August 2022 for studies investigating the value of serum sST-2 in the prediction of stroke incidence and post-stroke outcomes. Results: Nineteen articles were included. The articles reported conflicting results on the predictive value of sST-2 measurement in the incidence of stroke. Studies investigating the value of sST-2 measurement for the prognosis of post-stroke outcomes have reported positive associations between sST-2 levels and post-stroke mortality, composite adverse events, major disability, cerebral–cardiac syndrome, and cognitive impairment. Conclusions Although some studies have reported a predictive value of serum sST-2 measurement in the incidence of stroke, a clear consensus has yet to be reached because of discrepancies in the results. As for the prognosis of post-stroke outcomes, sST-2 may be a predictor of mortality, composite adverse events, and major disability after stroke. Overall, more well-designed prospective cohort studies are needed to reach a more decisive conclusion on the value of sST-2 measurement for the prediction of stroke and its outcomes and to determine optimal cutoffs.