Abstract Purpose: To investigate the protective mechanisms of propofol (Pro) on renal ischemia/reperfusion (I/R) injury by studying its impact on renal I/R endoplasmic reticulum stress. Methods: Eighteen male Sprague-Dawley rats (SD rats) were randomly divided into three groups: the I/R group, the Pro pretreatment group, and the control group, and corresponding treatments were performed. The levels of serum creatinine (Cr) and blood urea nitrogen (BUN) of each group were detected. The expression levels of CCAAT-enhancer-binding protein (C/EBP) homology protein (CHOP) and caspase-12 protein within renal tissue samples were detected by western blot. Results: The periodic acid-Schiff (PAS) staining was performed to observe the morphological changes within the renal tissues, and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay was performed to detect the presence of renal apoptosis. The Pro pretreatment significantly reduced the serum Cr and BUN levels, as well as the expressions levels of CHOP and caspase-12 protein inside the kidney of I/R rats, improving renal pathological injury and reducing the I/R-induced renal apoptosis. Conclusion: Propofol could downregulate the expression of stress-apoptotic proteins CHOP and caspase-12 in the endoplasmic reticulum, thus reducing renal I/R injury.