Objective To detect the contents of neuron-specific enolase (NSE) and phosphorylated tau (P-tau) in serum-derived exosomes of the elderly patients with type 2 diabetes mellitus (T2DM), and explore the correlation of them with mild cognitive impairment (MCI). Methods A total of 114 elderly T2DM patients admitted in our hospital from Jan. 2019 to Dec. 2020 were enrolled and assigned as the study subjects (study group), and another 100 healthy volunteers taking physical examination in the same period were assigned as the control group. Exosomes in the blood samples from the study subjects were extracted by ExoQuick-TC. Enzyme linked immunosorbent assay(ELISA) was used to detect the contents of NSE and P-tau in serum-derived exosomes. Mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) were employed to evaluate the cognitive status of the subjects. SPSS statistics 19.0 was used for data analysis. The data difference between groups was analyzed by student′s t test and Chi-square test. Spearman rank correlation analysis was adopted to study the correlation of NSE and P-tau contents in serum-derived exosomes with the severity of cognitive impairment. Receiver operating characteristic (ROC) curve was plotted to analyze predictive value of NSE and P-tau levels in serum-derived exosomes for MCI. Results The study group had significantly larger proportion of cognitive impairment, lower MMSE and MoCA scores, and higher incidence of MCI than the control group (all P<0.05). Based on the MoCA score, the 114 patients in the study group were further divided into MCI group (n=71) and non-MCI group (n=43). The levels of NSE and P-tau in serum-derived exosomes in MCI group were (13.27±1.61) μg/L and (17.14±2.45) pg/ml, which were significantly higher than those of the non-MCI group [(10.86±1.43) μg/L and (14.49±2.25) pg/ml; t=5.728,6.154; P<0.05]. Correlation analysis showed that the levels of NSE and P-tau in serum-derived exosomes were negatively correlated with MMSE score (r=-0.547, -0.562; P<0.05) and MoCA score (r=-0.583, -0.597; P<0.05) in the elderly T2DM patients. ROC curve analysis indicated that the area under the curve (AUC) of NSE level to predict MCI in elderly T2DM patients was 0.729, and that of P-tau level was 0.741. And, the AUC of their combination was 0.827, which was significantly higher than that of NSE (t=3.836, P<0.05) and p-tau (t=3.478, P<0.05) in the prediction of MCI. Conclusion Higher levels of NSE and P-tau in serum-derived exosomes are closely associated with the occurrence of MCI in elderly T2DM patients. Their combination has higher predictive value for the occurrence of MCI in the patients.