BACKGROUND: Ischemic cardiomyopathy (ICM) is the end stage of ischemic heart disease, in which ventricular remodeling contributes to a fatal ventricular arrhythmia, worsens heart function and unfavorable outcomes, and is related to persistent chronic inflammation. Low-intensity pulsed ultrasound (LIPUS) is an effective treatment modality for osteoarthropathy and has been illustrated to regulate the overactive inflammatory response in various diseases. Here, we aim to investigate whether LIPUS can perform cardiac protective effects in ICM and explore its possible mechanism. METHODS: The left anterior descending artery of adult male Sprague-Dawley rats was ligated for 4 weeks to develop ICM and then treated with LIPUS. Vagotomy was applied to suppress the cholinergic anti-inflammatory pathway. Cardiac-specific Cav-1 (caveolin-1) overexpression in ICM on arrhythmias, excitation-contraction coupling, and cardiac remodeling was investigated using the intramyocardial injection of an adeno-associated virus serotype 9 system. RESULTS: The results showed that LIPUS alleviated ventricular remodeling, improved cardiac electrophysiological function, and reduced the cardiac expression of collagens and inflammatory cytokines. Vagotomy suppressed the improvement of LIPUS. The overexpression of Cav-1 reset the influence of vagotomy. CONCLUSIONS: We found that LIPUS had a direct effect on regional anti-inflammation and antifibrosis, improved cardiac autonomic function and heart failure, protected the Cx43 (connexin-43) protein, and reduced the risk of malignant arrhythmia during ICM. The cholinergic anti-inflammatory pathway was one of the potential critical mechanisms involved, and Cav-1 might play an important role downstream. Our study provided a new, promising, and noninvasive strategy for treating ICM.