Objective To explore the effect of hypoxia-inducible factor-1α (HIF-1α) inhibitor LW6 on ferroptosis in septic cardiomyopathy rats. Methods Rat septic cardiomyopathy model was prepared using cecal ligation and puncture (CLP) method. Thirty-six specific pathogen-free (SPF) 6-8 weeks male SD rats were randomly divided into the sham-operated group, CLP group, CLP+solvent group, LW6 group, ferrostatin-1 (Fer-1) group, and LW6+Fer-1 group. The degree of myocardial damage in each group was evaluated through hematoxylin-eosin staining and detection of lactate dehydrogenase and creatine kinase content in cardiac tissue. Myocardial mitochondrial damage was observed by transmission electron microscopy. Ferroptosis level was determined by detecting iron ion concentration, reduced glutathione, malondialdehyde, and reactive oxygen species. Protein expression levels of HIF-1α, solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) in cardiac tissue were detected by Western blotting. Results Compared with the CLP group and the CLP+solvent group, the LW6 group could ameliorate myocardial damage, alleviate mitochondrial damage, inhibit ferroptosis-related indicators (all P<0.05), reduce HIF-1α protein expression levels (P<0.05), and enhance SLC7A11 and GPX4 protein expression levels (both P<0.05). Conclusion LW6 decreases HIF-1α expression and ferroptosis levels through the SLC7A11/GPX4 pathway, and ameliorates sepsis-induced cardiomyopathy.