Objective To explore the values of plasma levels of soluble semaphore 4D (sSema4D) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in the diagnosis and prognosis of the elderly patients with acute decompensated heart failure (ADHF). Methods A total of 102 elderly ADHF patients admitted to our hospital from June 2018 to June 2019 were enrolled as the ADHF group, and another 85 elderly patients undergoing physical examination during the same period were recruited as the control group. The plasma levels of sSema4D and NT-proBNP were compared between the two groups, and the receiver operating characteristic (ROC) curve was drawn to analyze the areas under the curve (AUC) of plasma sSema4D and NT-proBNP levels in the diagnosis of ADHF. After 1 year′s follow-up, according to the 1-year survival or death outcome, the DCHF patients were divided into survival group (n=79) and death group (n=23). ROC curve analysis was performed to analyze the prognostic value of plasma sSema4D and NT-proBNP levels. The correlation of the plasma levels with left ventricular ejection fraction (LVEF) was analyzed with Pearson linear analysis, and the prognostic risk factors were studied with Cox multivariate analysis. Results The plasma sSema4D and NT-proBNP of the ADHF patients were significantly higher than those of the control group, and the levels at discharge in the ADHF group were obviously higher than those on admission (P<0.05). The AUC of plasma sSema4D and NT-proBNP levels for the diagnosis of ADHF alone and in combination were 0.771,0.817, and 0.902, respectively. The plasma sSema4D and NT-proBNP levels were notably higher in the death group than the survival group (P<0.05). The AUC of plasma sSema4D and NT-proBNP alone and in combination to assess the prognosis of ADHF were 0.762,0.787,0.878, respectively. Pearson linear analysis showed that the plasma sSema4D and NT-proBNP levels were negatively correlated with LVEF in the ADHF patients (r=-0.726,－0.567; P<0.05). Cox multivariate analysis suggested that cardiac function classification, LVEF, plasma sSema4D and NT-proBNP levels were risk factors for the prognosis of patients with ADHF (P<0.05). Conclusion Plasma sSema4D and NT-proBNP levels are increased in ADHF patients, and they can be used as important indicators for the diagnosis and prognosis of the disease.