This study investigated the effects of heme oxygenase 1 (HO-1) on thrombomodulin (TM) and endothelial protein C receptor (EPCR) expression in sepsis-induced kidney injury. The role of HO-1 was evaluated in a cecal ligation and puncture (CLP)-induced model. Wistar rats were randomly assigned into four groups: sham, CLP, CLP + hemin (an HO-1 inducer), CLP + ZnPP (zinc protoporphyrin IX, an HO-1 inhibitor), and CLP + bilirubin. Compared with the sham group, the CLP group exhibited significantly elevated plasma levels of cystatin C, creatinine, urea nitrogen (blood urea nitrogen), tumor necrosis factor α, interleukin 1β, TM, and EPCR; lower plasma level of activated protein C, shorter prothrombin time and activated partial thromboplastin time; significantly increased microthrombus formation; and lower TM and EPCR mRNA and protein expression in the kidney. The administration of hemin lowered the plasma levels of cystatin C, creatinine, blood urea nitrogen, tumor necrosis factor α, interleukin 1β, TM, and EPCR; elevated plasma level of activated protein C; prolonged prothrombin time and activated partial thromboplastin time; attenuated microthrombus formation; and upregulated the expression of TM and EPCR and mRNA levels of TM and EPCR in the kidney in the CLP + hemin group. In contrast, ZnPP had the opposite effects. The results indicated that the enhanced induction of HO-1 increased the expression of TM and EPCR in the kidney and exerted an anticoagulant effect, thereby attenuating kidney injury in septic rats.