Objective To investigate the changes of serum neuron specific enolase (NSE), ferritin (SF) and bilirubin levels in the elderly patients with diabetic peripheral neuropathy (DPN) and explore their clinical significances. Methods Ninety patients with simple type 2 diabetes mellitus (T2DM group) and 90 patients with confirmed DPN (DPN group) hospitalized in our department from January 2016 to July 2017 were recruited in this study. Their levels of NSE, SF, total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), fasting blood glucose (FPG), glycosylated hemoglobin Alc (HbA1c), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG) were measured and compared between 2 groups. SPSS statistics 16.0 was used to analyze the data. According to the data type, Student′s t test or Chi-square test was used for intergroup comparison. Multivariate logistic regression analysis was employed to explore the independent risk factors for DPN. Receiver operating characteristic (ROC) curve was applied to analyze the cut-off points of NSE, SF and bilirubin in prediction of DNP. Results The levels of FPG, HbA1c, LDL-C, TC, TG, NSE and SF were significantly higher in the DPN group than the T2DM group, while those of HDL-C, TBIL, DBIL and IBIL were decreased significantly (P<0.05). Multivariate logistic regression analysis indicated that the increases of serum NSE, SF, FPG and HbA1c levels and the decreases of IBIL and HDL-C levels were independent risk factors for DPN in T2DM patients (P<0.05). ROC curve analysis showed that the best cut-off point, area under ROC curve (AUC), sensitivity and specificity of DPN predicted by NSE, SF and IBIL were 13.61μg/L, 0.855,9.33%, 80.26%; 589.6ng/ml, 0.782,1.30%, 73.26%; and 11.40mmol/L, 0.760,7.09%, 77.43%, respectively. Conclusion The occurrenceof DPN in T2DMpatients is affected by many factors. The increases of serum NSE and SF levels and the decreases of serum IBIL level may be related to its occurrence, and the detection of their levels may be of great significances in the diagnosis of DPN.