Objective To explore the predictive value of high-resolution vessel wall imaging (HR-VWI) combined with serum S100 calcium binding protein B (S100B) for the prognosis of patients with acute ischemic stroke (AIS). Methods A retrospective analysis was conducted on the clinical data of 82 AIS patients admitted to the 989th Hospital of the Joint Logistics Support Force from January 2021 to July 2025. According to the evaluation results of the modified Rankin scale (mRS) at 3 months after onset, the patients were divided into good prognosis group (n＝53, mRS score 0-2) and a poor prognosis group (n＝29, mRS score 3-6). Clinical data were compared between the two groups, and the predictive efficacy of HR-VWI combined with serum S100B for poor prognosis in AIS patients was evaluated. Results Compared with the good prognosis group, the poor prognosis group had significantly higher age, proportion of diabetes mellitus, plaque area, plaque enhancement degree, and serum S100B level (all P＜0.05). Multivariate analysis showed that advanced age, diabetes mellitus, large plaque area, high degree of plaque enhancement, and elevated S100B were independent risk factors for poor prognosis in AIS patients (all P＜0.05). Receiver operator characteristic (ROC) curve analysis revealed that the area under the curve (AUC) of serum S100B, plaque area, plaque enhancement degree alone, and their combination for predicting poor prognosis in AIS patients were 0.820, 0.788, 0.804, and 0.933, respectively (all P＜0.05). Conclusion Abnormally elevated serum S100B in AIS patients, combined with HR-VWI parameters, presents satisfactory predictive efficacy for 3-month outcomes, and serves as a valid indicator for prognostic stratification of AIS cases admitted within 7 days of onset.