Elevated body temperature above normal level during infection, environmental factors, and drug-treatment interfere with body function especially nervous tissues. The present study illustrates the effects of experimental hyperthermia in the brain of rat especially cerebrum and cerebellar region. Eighty fertile male Wistar rats were arranged into four groups; control, and hyperthermic-treatment groups for 14, 28, and 42 days. The body temperatures were elevated 4°C above normal body temperature by placement in a dry-air incubator at 42-43°C for 1 hour daily. At the end of treatment, the animals were sacrificed and subjected for investigations of light and transmission electron microscopy, neurotransmitters, antioxidant enzymes, malondialdydes, caspase-7 and DNA fragmentation. The present findings revealed marked increase of oedematous lesions associated with neuronal cell damage in both brain regions. Cerebellar cortex exhibited massive degeneration of Purkinje cells and demyelination. Atrophy of mitochondria, vesicuolation of rough endoplasmic reticulum and apparent loss of ribosomes. The cytopathological alterations coincides with marked depletion of neurotransmitters and antioxidant enzymes glutathione peroxidase, catalase and superoxide dismutase and increase of apoptic markers including malondialdhyde and caspase-7 and confirmed DNA fragmentation. The authors finally concluded that elevated body temperature interfered with depletion of neuronal cell function assessed by depletion of neurotransmitters and decreased antioxidant enzymes and increase cell damage.