Myocardial ischemia-reperfusion (I/R) injury remains a critical clinical challenge, driven by unresolved inflammation and oxidative stress. This study investigated the cardioprotective effects of engeletin (ENG), a flavonoid glycoside, in mitigating myocardial I/R injury through modulation of zinc and redox homeostasis. In a murine I/R model, ENG administration significantly improved cardiac functon(enhanced LVEF and LVFS), reduced infarct size (TTC staining), attenuated apoptosis (BAX, cleaved Caspase3, and TUNEL), and suppressed adverse remodeling (Masson staining). Mechanistically, integrated transcriptomic and metabolomic profiling in bone marrow-derived macrophages (BMDMs) revealed that ENG suppressed oxidative stress pathways while enhancing glutathione metabolism. Limited proteolysis mass spectrometry (LiP-MS) identified VPS35, a retromer complex component, as ENG’s direct target. ENG competitively disrupted the VPS35-ZNT1 interaction, thereby maintaining ZNT1 membrane localization to promote zinc efflux and prevent cytosolic zinc overload—a key driver of NLRP3 inflammasome activation. Molecular dynamics simulations and mutagenesis (GLN566A mutation in VPS35) confirmed that ENG binding stabilized VPS35’s Armadillo domain, blocking ZNT1 internalization. These findings highlighted ENG's dual antioxidative and anti-inflammatory roles via the VPS35-SLC30A1 axis, positioning it as a novel therapeutic agent for I/R injury. The study bridged flavonoid pharmacology with macrophage immunometabolism, offering a translational strategy to improve post-infarct outcomes.