This study aims to investigate the protective effects of avicularin (AVL) against myocardial ischemia-reperfusion (I/R) injury via inhibition of ferroptosis, and to elucidate its underlying molecular mechanisms. Rats were randomly assigned to three groups: sham-operated (Sham), I/R, and AVL. Electrocardiographic monitoring was performed to assess the cardiac electrical activity of rats. The serum levels of B-type natriuretic peptide (BNP) and cardiac troponin T (cTnT) were measured using ELISA. Cardiac function, including left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-systolic volume (LVESV), and left ventricular end-diastolic volume (LVEDV), was evaluated by echocardiography. HE staining was conducted to examine myocardial histopathological alterations, while transmission electron microscopy was employed to observe mitochondrial ultrastructural changes. Commercial assay kits were used to determine the ratio of reduced to oxidized glutathione (GSH/GSSG), malondialdehyde (MDA), and Fe²⁺content in myocardial tissue. Western blot was performed to analyze the protein expression levels of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), acyl-CoA synthetase long-chain family member 4 (ACSL4), and hypoxia-inducible factor-1 alpha(HIF-1α). To further verify the involvement of the HIF-1α/SLC7A11/ GPX4 signaling pathway, the HIF-1α inhibitor riociguat was used to evaluate the regulatory effect of AVL.The results showed that AVL treatment markedly improved myocardial histopathological alterations and preserved mitochondrial ultrastructure. Compared with I/R group, AVL significantly reduced the levels of BNP, cTnT, LVESV, MDA, Fe²⁺ and the protein expression of ACSL4 (P<0.05 or P<0.01). Conversely, AVL treatment significantly increased LVEF, LVFS, the GSH/GSSG ratio, and the protein expression of GPX4, SLC7A11, FTH1, and HIF-1α (P<0.01), while LVEDV remained unchanged (P>0.05). Compared with AVL group, riociguat administration reversed these effects, resulting in elevated levels of Fe²⁺, MDA, BNP, and cTnT (P<0.05 or P<0.01), and a significant reduction in HIF-1α, SLC7A11 and GPX4 protein expression (P<0.01).These findings suggest that AVL mitigates myocardial I/R injury by activating the HIF-1α/SLC7A11/GPX4 signaling pathway to suppress ferroptosis.