Hydroxyl Safflower Yellow A (HSYA) is the primary bioactive compound derived from Safflower, which has been scientifically proven to possess anti-inflammatory, anti-apoptotic, and ameliorative properties against mitochondrial damage during acute myocardial ischemia-reperfusion injury (MIRI); however, its effects during the recovery stage remain unknown. Angiogenesis plays a crucial role in the rehabilitation process. The objective of this study was to investigate the long-term angiogenic effect of HSYA and its contribution to recovery after myocardial ischemia, as well as explore its underlying mechanism using non-targeted metabolomics and network pharmacology. The MIRI model in rat was established by ligating the left anterior descending branch of the coronary artery. The effect of HSYA was assessed based on myocardial infarction volume and histopathology. Immunofluorescence staining was employed to evaluate angiogenesis, while ELISA was used to detect markers of myocardial injury. Additionally, a rat myocardial microvascular endothelial cell (CMECs) injury model was established using oxygen-glucose deprivation/reoxygenation (OGD/R), followed by scratch assays, migration assays, and tube formation experiments to assess angiogenesis. Western blot analysis was conducted to validate the underlying mechanism. Our findings provide compelling evidence for the therapeutic efficacy of HSYA in reducing myocardial infarction size, facilitating cardiac functional recovery, and reversing pathological alterations within the heart. Furthermore, we elucidate that HSYA exerts its effects on promoting migration and generation of myocardial microvascular endothelial cells through activation of the HIF-1α-VEGFA-Notch1 signaling pathway. These results underscore how HSYA enhances cardiac function via angiogenesis promotion and activation of the aforementioned signaling cascade.