Energy drink (ED) is popular and widely consumed among athletes and young adults. This study was design to assess the effects of caffeinated energy drink on neuro-histo-architecture of frontal cortex (FC), lipid peroxidation, antioxidant enzymes and astrocyte proliferation. Twenty (25) adult male Wistar rats were divided as follows (n=5); Group A= Control, Group B= 2ml of energy drinks for 21days, Group C=2ml of energy drinks for 21days + 7days withdrawal, Group D= 4ml for 21days and Group E= 4ml of energy drinks for 21days + 7days withdrawal. ED was given orally. Superoxide Dismutase (SOD) and Malondialdehyde (MDA) activities were assayed in the brain and serum, brain tissue was processed for histology and astrocytes immunohistochemistry. Results obtained show that ED treatment group had dose-dependent effects on neuronal morphology disruptions, vacuolation in the neuropil, loss of Nissl granules and necrotic neurons compared with the control and recovery groups characterized by normal neurons and gradually regenerating neurons. Astrocytic proliferation seen in the ED treated groups as compared to the Groups A, C and E. MDA activity increased in both brain and serum of ED treated group as compared with the control @ P<0.05. SOD in brain and serum increase significantly in Groups B and D as to compared to A, C and D at P<0.05. The ratio of MDA to SOD activity shows that MDA increased significantly compared with the SOD in all the ED treatment groups. Caffeinated energy drink has the ability to potentiate oxidative stress in neurons while activating anti-inflammatory response of glia cells, withdrawal aids neuron regeneration.