Objective To explore the mechanism of astragaloside A (AS) in alleviating myocardial injury in rats with myocardial infarction in diabetes mellitus (DM) based on nuclear factor E2-related factor 2 (NRF2)/ferroportin 1 (FPN1) pathway. Methods DM rat model was established by high sugar diet and streptozotocin (STZ). The 50 rats successfully modeling DM was giving ligating the anterior descending branch of left coronary artery to establish the rat model of DM myocardial infarction. The 50 rats with successful modeling were randomly divided into infarction group, low dose AS (AS-L, 20 mg/kg AS), middle dose AS (AS-M, 40 mg/kg AS), high dose AS (AS-H, 80 mg/kg AS) group, and AS-H+NRF2 inhibitor (ML385, 80 mg/kg AS+30 mg/kg ML385) group. Meantime, 10 open chest rats were taken as the sham operation group. After the intervention, cardiac function ［left ventricular ejection fraction (LVEF), creatine kinase isoenzyme-MB (CK-MB), creatine kinase (CK)］ indexes were measured; 2, 3, 5-triphenyltetrazolium chloride (TTC) was used to measure the volume ratio of myocardial infarction. The kit was used to detect the iron content level; HE staining was used to detect the pathological changes of myocardium in rats. mRNA and proten expression of NRF2, glutathione peroxidase 4 (GPX4) and FPN1 in myocardium eve analyzed by qRT-PCR and Western blot. Results Compared with the sham operation group, the pathological injury of rats in the infarction group was serious, the expression of LVEF, mRNA and protein expression of NRF2, GPX4 and FPN1 decreased obviously, the infarct volume ratio, iron ion content, CK-MB and CK increased obviously (P<0.05). Compared with the infarction group, the pathological injury of rats in AS-L group, AS-M group and AS-H group was improved, the expression of LVEF, mRNA and protein expression of NRF2, GPX4 and FPN1 increased obviously, the infarct volume ratio, iron ion content, CK-MB and CK decreased obviously, they were dose dependent (P<0.05). Compared with the AS-H group, the pathological injury in the AS-H+ML385 group was relatively serious, the expression of LVEF, mRNA and protein expression of NRF2, GPX4 and FPN1 decreased obviously, the infarct volume ratio, iron ion content, CK-MB and CK increased obviously (P<0.05). Conclusion AS can alleviate the myocardial injury of DM myocardial infarction rats, which may be achieved by activating NRF2/FPN1 pathway to inhibit iron death