Ferroptosis is a critical contributor to cardiomyocyte injury in acute myocardial infarction (AMI). This study aimed to identify key ferroptosis-associated genes and elucidate their roles in AMI. Transcriptomic datasets from AMI patients and healthy controls were analyzed to identify differentially expressed genes (DEGs). The role of the solute carrier family 11 member 1 (SLC11A1) was validated in vitro using a hypoxia/reoxygenation (H/R) model in H9c2 cardiomyocytes and in vivo using a murine AMI model. SLC11A1 expression was elevated in H/R-treated cardiomyocytes and infarcted murine hearts. SLC11A1 silencing reduced infarct size and improved cardiac function, and suppressed ferroptosis. Mechanistically, SLC11A1 led to the transcriptional suppression of glutathione peroxidase 4 (GPX4) mediated by the transcription factor specificity protein 1 (Sp1). This study identifies the SLC11A1-Sp1-GPX4 axis as a pivotal transcriptional regulator pathway driving ferroptosis in AMI. These findings highlight SLC11A1 as a promising therapeutic target in AMI.