Millettia pulchra Kurz var-laxior (Dunn) Z. Wei, a wild-growing plant of the family Fabaceae is known to possess multifarious medicinal properties. 17-Methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) is a flavonoid monomer extracted from its root, which has been used in traditional Chinese medicine, with a long history as a remedy of hypertension and cardiovascular remodeling. The present study was conducted to further investigate the regulatory mechanisms of MHBFC based on the endothelial nitric oxide synthase-nitric oxide (eNOS-NO) signaling pathway. The abdominal aorta of the male Sprague–Dawley rats was narrowed to induce cardiac remodeling, and the rats were given corresponding drugs for 6 weeks after operation. At the end of the experiment, the relevant indexes were detected. The results showed that N^ω-nitro-L-arginine methyl ester (L-NAME) could increase the myocardial cell cross-section area, myocardial fibrosis, and the cardiac collagen volume fraction. The serum NO and eNOS levels and the expression of p-eNOS, p-PI₃K and p-Akt protein were decreased, and myocardial microvascular endothelial cell (MMVEC) apoptosis increased. However, the above changes were reversed after treatment with MHBFC. These results indicated that MHBFC could increase eNOS protein phosphorylation by increasing PI₃K and Akt protein phosphorylation, and activated the eNOS-NO signaling pathway, increased eNOS enzyme activity, catalyzed the generation of protective NO, and counteracted MMVEC apoptosis induced by cardiac remodeling, thereby protecting against myocardial damage and reversing cardiac remodeling.