Objective To investigate the therapeutic effectiveness of levosimendan on acute exacerbation of heart failure with preserved ejection fraction (HFpEF) in the elderly. Methods A retrospective analysis was carried out in 52 elderly patients with acute exacerbation of HFpEF admitted to the First Affiliated Hospital of Air Force Medical University from January 2016 to December 2019. The patients were divided into the levosimendan treatment group (26 cases) and the control group (26 cases) according to whether they received levosimendan therapy. The improvement of New York Heart Association (NYHA) cardiac function classification (effective rate) 1 week after treatment, the rehospitalization rates within 3 and 12 months, and the changes of N-terminal pro-brain natriuretic peptide (NT-proBNP) before and after treatment were compared between the 2 groups. SPSS statistics 19.0 was used for data analysis. According to the distribution type, student′s t test, Wilcoxon rank sum test, Chi-square test or Fisher exact probability test was performed for intergroup comparison. Results Compared with the control group, the levosimendan group had significantly higher effective rate after 1 week treatment (P<0.05) and lower readmission rate within 3 months (P<0.05). There was no statistical difference in the readmission rate within 12 months between the 2 groups (P>0.05). After treatment, the NT-proBNP levels were significantly decreased in both groups (P<0.05), but the difference was not statistically significant (P>0.05). After treatment, the proportion of patients whose NT-proBNP level was decreased by more than 30% in the two groups were compared, but no statistical difference was observed between the 2 groups (P>0.05). Conclusion Application of levosimendan in the treatment of acute exacerbation of HFpEF in the elderly can significantly alleviate the symptoms of heart failure, improve the heart function and reduce short-term readmission risk, with high safety, but has no obvious effect on long-term readmission risk.