Background: Heart failure (HF) is a leading cause of morbidity and mortality worldwide, characterized by progressive myocardial remodeling, cardiomyocyte loss, and impaired cardiac function. Astragaloside IV (AS), a bioactive compound derived from Astragalus membranaceus, shows cardioprotective effects but is limited in clinical application due to poor solubility and low bioavailability. Methods: An acid-responsive metal organic framework (MOF)-based nanoplatform was developed for targeted delivery of AS. The system was characterized using transmission electron microscopy, dynamic light scattering, drug loading analysis, and in vitro release profiling. In vitro efficacy was evaluated in Angiotensin II-induced H9c2 cardiomyocytes by assessing cell viability, hypertrophic markers (brain natriuretic peptide, atrial natriuretic peptide, β-myosin heavy chain), and cellular morphology. In vivo therapeutic effects were assessed in a transverse aortic constriction (TAC)-induced HF mouse model using echocardiography, serum biomarkers, and histological analysis. The involvement of apoptosis, angiogenesis, and PI3K/Akt signaling was evaluated by Western blotting. Results: The nanoplatform exhibited uniform nanoscale size, high drug loading, excellent colloidal stability, and pH-responsive release with enhanced drug liberation under acidic conditions. It significantly improved cardiomyocyte viability, suppressed hypertrophic gene expression, reduced myocardial injury and fibrosis, and improved cardiac function, including increased ejection fraction and fractional shortening. Mechanistically, it inhibited cardiomyocyte apoptosis, promoted angiogenesis, and activated the PI3K/Akt signaling pathway. Furthermore, the system also showed excellent hemocompatibility and negligible systemic toxicity. Conclusions: This acid-responsive nanoplatform significantly enhances the therapeutic performance of AS and provides a promising strategy for precision nanomedicine-based intervention in HF.