Objective To investigate the expression and clinical significance of serum forkhead box protein O3a (FOXO3a) and platelet-derived growth factor (PDGF) in patients with type 2 diabetes mellitus and diabetic peripheral neuropathy (DPN).Methods A total of 110 patients with type 2 diabetes mellitus admitted to our hospital from December 2020 to December 2022 were selected, and were divided into non-DPN (NDPN) group (45 cases) and DPN group (65 cases) according to whether they were complicated by DPN. Another 30 healthy people who underwent health checkup during the same period in our hospital were randomly selected as the control group (NC group). The general information and data on biochemical indicators including blood lipids and glucose were collected. ELISA was used to detect the serum levels of FOXO3a and PDGF of patients in the three groups. The receiver operating characteristic (ROC) curve was applied to analyze the predictive values of serum levels of FOXO3a and PDGF for the occurrence of DPN in type 2 diabetes mellitus.Results The age of patients and the disease course were different among the three groups (P < 0.05), while there was no statistically significant difference in sex composition, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and levels of alanine aminotransferase, aspartate aminotransferase, creatinine, and urea nitrogen among the groups (P > 0.05). There was no significant difference between the NDPN group and the DPN group in proportions of patients with atherosclerosis, retinopathy, history of antihypertensive drug use, insulin injection, and metformin use (P > 0.05). There was no statistically significant difference in levels of TC, TG, LDL-C, HDL-C, FCP and ABI among the three groups (P > 0.05). Compared with the NC group, the levels of HbAlc and FPG were higher in the NDPN group and the DPN group (P < 0.05). Compared with the NDPN group, the levels of MNCV and SNCV were lower in the DPN group (P < 0.05). Compared with the NC group, the levels of FOXO3a and PDGF were higher in the NDPN group and the DPN group (P < 0.05). Compared with the NDPN group, the levels of FOXO3a and PDGF were even higher in the DPN group (P < 0.05). ROC curve analysis showed that the areas under the curves (AUCs) of serum FOXO3a, PDGF and their combined detection for predicting DPN in diabetic patients were 0.695 (95% CI: 0.590, 0.779), 0.636 (95% CI: 0.539, 0.726), and 0.732 (95% CI: 0.639, 0.812), with the sensitivities being 80.00% (95% CI: 0.733, 0.848), 92.31% (95% CI: 0.856, 0.977), and 89.23% (95% CI: 0.838, 0.954), and the specificities being 55.56% (95% CI: 0.438, 0.654), 33.33% (95% CI: 0.238, 0.452), and 51.11% (95% CI: 0.416, 0.597), respectively.Conclusion The abnormal serum levels of FOXO3a and PDGF in patients with type 2 diabetes mellitus and DPN suggest their associations with the occurrence and progression of DNP in type 2 diabetes mellitus.