Objective To investigate the value of soluble growth STimulation expressed gene 2 (sST2) combined with N-terminal pro-B-type natriuretic peptide (NT-proBNP) to evaluate the prognosis of elderly patients with heart failure with mid-range ejection fraction (HFmrEF) after sacubitril-valsartan (SV) intervention. Methods A total of 81 HFmrEF patients admitted to our hospital from April 2018 to April 2020 were recruited in and treated with SV intervention. The risk factors affecting the occurrence of composite endpoints in HFmrEF patients with SV treatment were analyzed, and the value of sST2 combined with NT-proBNP for the prognosis of HFmrEF patients after SV intervention was evaluated. SPSS statistics 26.0 was used for data analysis. According to the data types, student′s t test, Rank sum test, Chi-square test or Fisher exact test was performed for comparison between groups. Cox hazards model was used to analyze the relationship between composite endpoints and variables. Results After 6 months of follow-up, 19 patients experienced composite endpoints and were included in the composite endpoint group, and the remaining 62 patients were included in the non-composite endpoint group. The composite endpoint group had significantly higher heart rate, lower serum creatinine, higher sST2 and NT-proBNP levels, larger left atrial diameter, and larger proportions of smoking history, PCI or thrombolysis history, and acute myocardial infarction history when compared with the non-composite endpoint group (P<0.05). Univariate and multivariate Cox regression analyses showed that sST2 and NT-proBNP levels were independent risk factors for composite endpoints in HFmrEF patients after SV treatment (P<0.05). Receiver operating characteristic (ROC) curve analysis indicated that the diagnostic value of sST2 combined with NT-proBNP was higher than that of a single index in predicting composite endpoint events. Conclusion sST2 combined with NT-proBNP has a significant predictive value for the prognosis of elderly HFmrEF patients after SV intervention.