BACKGROUND: Erectile dysfunction (ED) is a significant health issue affecting the global male population, with a complex and multifaceted etiology. High-fat diet (HFD) is known to impair endothelial function and promote the development of ED. Hinokiflavone (HINO), a naturally occurring biflavonoid, has garnered attention for its notable antioxidant and anti-inflammatory activities, suggesting its potential therapeutic role in treating ED. AIM: This study aims to investigate the therapeutic effects and underlying mechanisms of HINO in HFD-induced ED. METHODS: Network pharmacology and molecular dynamics simulation were employed to predict relevant targets and analyze their binding kinetics. Rat corpus cavernosum endothelial cells (RCCECs) were treated with palmitic acid to induce metabolic dysfunction. The ED model was established by feeding male rats an HFD (60 kcal% fat). OUTCOMES: The primary outcomes were the target genes and pathways associated with HINO and the evaluation of its therapeutic potential in HFD-induced ED. RESULTS: Bioinformatics analyses identified the epidermal growth factor receptor (EGFR) and protein kinase B (Akt) as key molecular targets of HINO. Treatment with HINO promoted RCCEC proliferation, enhanced antioxidant activities, and increased nitric oxide production. The administration of HINO ameliorated erectile dysfunction, improved serum lipid profiles, and reduced oxidative stress in HFD-fed rats. The protective effects of HINO against endothelial dysfunction and impaired cell viability were mediated through modulation of the EGFR/PI3K/Akt/eNOS signaling pathway. CLINICAL TRANSLATION: The results provide a strong rationale for further investigation of HINO as a novel therapeutic agent for ED, with promising implications for future clinical applications. STRENGTHS AND LIMITATIONS: In this study, we found that HINO could mitigate HFD-induced ED. Limitations of the study include that the alternative mechanisms of HINO were not fully explored in these settings. CONCLUSIONS: Our findings underscore the pharmacological properties of HINO in the management of ED, particularly through the modulation of critical targets such as EGFR.