Background Cardiovascular diseases represent major concerns in postmenopause. This study explores the therapeutic potential of naringenin nano-emulsion (nNAR) in mitigating postmenopausal cardiovascular complications induced by estrogen deficiency and a high-fat diet in rats. The methodology integrated network pharmacology, molecular docking, and in vivo experiments to accomplish this objective. Methods Molecular targets of naringenin (NAR), alongside those linked to estrogen deficiency and hypertension, were sourced from relevant databases. The intersecting targets were identified to construct the “drug-target-disease” network that delineates core targets. Subsequently, molecular docking was conducted to evaluate the interaction between NAR and the primary target. In the in vivo study, adult female rats underwent ovariectomy and were placed on a high-fat diet for 30 weeks. For the last 6 weeks, NAR suspension and nNAR were administered orally on a daily basis, in conjunction with estradiol injections given every four days. Endpoint assessments included measurements of blood pressure, cardiac function, and cardiac oxidative and inflammatory status. Additionally, levels of angiotensin II (Ang II), its receptor (AT1R), cardiac transforming growth factor beta-1 (TGF-β1), mothers against decapentaplegic homolog 3 (Smad-3), and matrix metalloproteinase-9 (MMP-9) were quantified, accompanied by cardiovascular histological analysis. Results nNAR significantly mitigated hypertension and molecular cardiomyopathy, downregulated the Ang II/AT1R/TNF-α/TGF-β1/Smad-3/MMP-9 signaling pathway and ameliorated oxidative stress. Overall, the efficacy of nNAR was comparable to that of estradiol and surpassed that of NAR suspension. Conclusion nNAR exhibits anti-hypertensive action through antioxidant, anti-inflammatory and anti-profibrotic activities in the hearts of ovariectomized rats by inhibiting Ang II, AT1R, TNF-α, TGF-β1, Smad-3 and MMP-9.