Purpose To investigate 4-HNE expression in diabetic rat kidneys and the protective effect of probucol. Methods Diabetic rat models were established. Diabetic rats with successful modeling were randomly divided into the diabetic group (group D) and probucol treated group (group P). Normal rats were put into the control group (group C). Rats in group P were treated with probucol (110 mg/kg day), and rats in groups D and C were given equal volume of water instead. Serum creatinine (SCr), urea nitrogen (BUN), triglyceride (TG), total cholesterol (TC), and 24-h urinary protein were measured at the 4th, 8th, and 12th weeks. Periodic acid-schiff (PAS) staining and hematoxylin-eosin (HE) staining were used to evaluate the renal pathological changes. The immunohistochemistry and Western-blot were used to detect 4-HNE expression in renal tissue. Results The SCr, BUN, TG, TC, and 24-h urinary protein in group D increased in the 4th, 8th, and 12th weeks and were higher than those in group C (P < 0.05). The SCr, BUN, TG, TC, and 24-h urinary protein in group P decreased compared to group D (P < 0.05). Pathological kidney changes in group D were more serious than those in group P. The level of 4-HNE expression in group D significantly increased at the 4th, 8th, and 12th weeks and were higher than those in group C (P < 0.05). In the kidneys treated with probucol, the level of 4-HNE significantly decreased compared to group D (P < 0.05). Conclusions Probucol can protect the diabetic kidney by decreasing 4-HNE expression and lipid peroxidation levels.