Abstract Objective: To investigate the mechanism of remifentanil (Rem) on myocardial fibrosis in rats with dilated cardiomyopathy (DCM) through interleukin-6 (IL-6) /signal transducer and activator of transcription3 (STAT3)/glutathione peroxidase 4 (GPX4) pathway. Methods: DCM rat model was established by intraperitoneal injection of 2.5 mg/kg doxorubicin, which were assigned into , Model Group（Model）, low-dose Rem group (Rem-L, 2 μg/kg), medium-dose Rem group (Rem-M, 4 μg/kg), high-dose Rem group (Rem-H, 8 μg/kg), and high-dose Rem+Colivelin (STAT3 activator) group (Rem-H+Colivelin, 8 μg/kg Rem+1 mg/kg Colivelin), each with 12 rats. Another 12 normal Wistar rats were set as Control group（Control）. After 4 weeks of continuous administration, Siemens ultrasound was used to measure Left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular brachyaxis shortening rate (LVFS),. Immunohistochemistry was used to detect type I collagen (Col I), and transforming growth factor-β1 (TGF-β1), type III collagen (Col III) in myocardial tissue. Masson staining and HE were used to detect pathological changes in myocardial tissue. Western blot was performed to detect IL-6/STAT3/GPX4 pathway related proteins. Results: Compared with Control group, the Model group showed obvious increases in LVEDD, LVESD, Col I, Col III, TGF-β1, IL-6, and p-STAT3Tyr705/STAT3 in myocardial tissue, great decreases in LVEF, LVFS, SLC7A11, and GPX4 (P<0.05), and inflammatory infiltration, collagen accumulation, and myocardial fibrosis. Compared with Model group, Rem-M and Rem-H groups showed great reductions in LVEDD, LVESD, Col I, Col III, TGF-β1, IL-6, and p-STAT3Tyr705/STAT3 in myocardial tissue, obvious increases in LVEF, LVFS, SLC7A11, and GPX4 (P<0.05), and improvement in myocarditis injury and fibrosis. Colivelin was able to reverse the improvement effect of Rem on myocardial fibrosis in DCM rats. Conclusion: Rem may reduce collagen accumulation, improve myocardial fibrosis and cardiac function in DCM rats by adjusting IL-6/STAT3/GPX4 pathway.