Objective To investigate the mechanism of remifentanil (Rem) on myocardial fibrosis in rats with dilated cardiomyopathy ( DCM) in relation to the interleukin-6 ( IL-6) / signal transducer and activator of transcription 3 (STAT3) / glutathione peroxidase 4 (GPX4) pathway. Methods A DCM rat model was established by intraperitoneal injection of 2. 5 mg / kg doxorubicin. The rats were then divided into Model, low-dose (Rem-L, 2μg / kg), medium-dose (Rem-M, 4 μg / kg), and high-dose Rem groups (Rem-H, 8 μg / kg), and a high-dose Rem+Colivelin (STAT3 activator, Rem-H+Colivelin, 8 μg / kg Rem+1 mg / kg Colivelin) group (n = 12 rats per group).Another 12 normal Wistar rats were set as a Control group. After continuous administration for 4 weeks, left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter ( LVEDD), and left ventricular fractional shortening ( LVFS) were measured by ultrasound. Type Ⅰ collagen ( Col Ⅰ), transforming growth factor-β1 ( TGF-β1), and type Ⅲ collagen ( Col Ⅲ) expression in myocardial tissue were detected by immunohistochemistry. Pathological changes in myocardial tissue were detected by Masson and hematoxylin / eosin staining. IL-6/ STAT3 / GPX4 pathway-related proteins were detected by Western blot. Results Compared with the Control group, rats in the Model group showed obvious increases in LVEDD, LVESD,ColⅠ((123. 62±10. 78) vs (76. 53±6. 12)), ColⅢ, TGF-β1, IL-6, and phospho-STAT3^Tyr705/ STAT3((0. 95±0.05) vs (0. 46±0. 92)) in myocardial tissue, and decreases in LVEF(( 52. 19± 4. 88)% vs ( 76. 78± 6. 97)%),LVFS, SLC7A11, and GPX4 ((0. 11± 0. 01) vs ( 0. 43± 0. 04)) ( P<0. 05), inflammatory infiltration, collagen accumulation, and myocardial fibrosis. Compared with the Model group, rats in the Rem-M and Rem-H groups showed reduced LVEDD, LVESD, ColⅠ((98. 74±7. 28)、(84. 27±7. 13) vs (123. 62±10. 78)), ColⅢ, TGF-β1,IL-6, and p-STAT3 ^Tyr705/ STAT3((0. 81±0. 06)、(0. 57±0. 04) vs (0. 95±0. 05)) in myocardial tissue, increases in LVEF((69. 85±6. 13)%、(72. 83±6. 55)% vs(52. 19±4. 88)%), LVFS, SLC7A11, and GPX4((0. 24±0. 02)、(0. 36±0. 02) vs (0. 11± 0. 01)) (P<0. 05), and improvements in myocarditis injury and fibrosis. Colivelin was able to reverse the improving effect of Rem on myocardial fibrosis in DCM rats. Conclusions Rem may reduce collagen accumulation and improve myocardial fibrosis and cardiac function in DCM rats by adjusting the IL-6/STAT3 / GPX4 pathway.