Background: The aim of this study was to investigate the effects of nano-eugenol combined with aerobic exercise against the streptozotocin toxicity and inflammatory mediators P38-MAPK, NPY and A-Rα2A in the dorsal root ganglia of diabetic rats. Methods: Twenty-five, 8-week-old Wistar male rats were divided into 5 groups: 1) normal control group (normal model); 2) diabetic control group (diabetic model); 3), diabetic + exercise group (diabetic+exercise model); 4) diabetic group + nano-eugenol (diabetic+nano model); and 5) diabetic + exercise + nano-eugenol (diabetic+exercise+nano model). Diabetes was induced in the experimental groups 2 through 5 by the intraperitoneal injection of streptozotocin at 4mg/100 grams of the rats’ body weight. The nano-eugenol supplement was also gavaged into the supplement groups 4 and 5 only. Groups 3 and 5 exercised progressively at a speed of 8 to 20 meter/min for 5 to 30 min, five days a week over the 8-week study duration. Results: The diabetic rats that exercised and were treated with the nano-eugenol, showed a significant decrease in P38-MAPK gene expression compared to the normal model group (P=0.001). The study of the therapeutic modalities also showed that only the diabetic + exercise + nano-eugenol group showed a significant increase in NPY and A-Rα2A genes compared to the normal model (P=0.001). Conclusion: Based on the results, the use of nano-eugenol supplementation combined with aerobic exercise is likely to be effective in controlling the neurological damages due to diabetes by negatively regulating the P38-MAPK gene while positively regulating the NPY and A-Rα2A genes in the DRG region.