This study examines the neuroprotective and antioxidant effects of ethanolic extract (UDExt) and melatonin (Mel) in mitigating chlorpyrifos (CPF)-induced toxicity in rats, with melatonin serving as a standard antioxidant. Male rats were divided into six groups: (I) Control, (II) UDExt (200 mg/kg), (III) Mel (20 mg/kg), (IV) CPF (10 mg/kg), (V) UDExt + CPF, and (VI) Mel + CPF. UDExt and Mel were administered for 7 days prior to CPF exposure, followed by a treatment of 14 days. The findings revealed that CPF exposure significantly impaired hematological parameters (WBC, PLT, LYM), increased lipid peroxidation and protein oxidation, and decreased antioxidant enzyme activities (SOD, CAT, GPx) in brain and cerebellar tissues compared to control rats. Behavioral tests, including the open field test, showed that CPF reduced locomotor activity and increased anxiogenic symptoms. The Y-maze test revealed impaired recognition memory, and the tail suspension test indicated increased depressive symptoms. Histological analysis revealed neuronal damage in the brain and cerebellum tissues. Treatment with UDExt or melatonin, following CPF exposure, significantly improved hematological parameters, reduced lipid peroxidation and protein oxidation, normalized antioxidant enzyme activities, and alleviated neurobehavioral alterations. Histopathological analysis also showed that UDExt or melatonin combined with CPF notably reduced neuronal damage in the brain and cerebellum. UDExt and melatonin mitigated the CPF-induced neurobehavioral alterations associated oxidative injury.