Introduction: There are extensive people exposures to paraquat (PQ) herbicide resulting in human health hazards. Aim of the Work: To compare the beneficial neuroprotective effects of hesperidin and benfotiamine on paraquat (PQ)-induced spinal cord neurotoxic effects in rats. Materials and Methods: Rats were divided into 4 groups as following: control, paraquat (PQ 20.8 mg/kg, oral gavage (e.g.)), paraquat + benfotiamine (50 mg/kg, oral gavage (e.g.)) and paraquat + hesperidin (40 mg/kg, oral gavage (e.g.)). PQ is given as the previous dose. Rats are treated 6 days per week. Results: There was a significant increased mean value of malondialdehyde associated with a significant reduction in the content of reduced glutathione and antioxidant enzymes activities associated with a significant increase in Serum phosphorylated neurofilament-H, neurospecific enolase and s100 levels were recorded and significant spinal cord histopathological changes in paraquat treated group as compared to their corresponding values in the control group and immunohistochemical examination confirmed these results. Upon supplementation with benfotiamine and hesperidin to paraquat treated rats, there was a significant decrease in the mean values of malondialdehyde associated with a marked increase in the content of reduced glutathione and antioxidant enzymes activities associated with a significant decrease in Serum phosphorylated neurofilament-H, neurospecific enolase and s100 levels were also recorded with significant improvement of spinal cord architecture when compared with the paraquat treated group. Conclusion: The use of benfotiamine and hesperidin produced a significant protection against all of the above-mentioned changes.