The present study aimed to demonstrate the ameliorative effects of omega-3, melatonin, and their combination against AlCl3 induced oxidative stress in the brain (cerebrum and cerebellum) of albino rats. As well as to study the effects of AlCl3, omega-3, melatonin, and their combination on biochemical parameters like (OS, lipid peroxidation, and AD) markers in brain supernatant of experimental rats. Forty adult female rats were used in this present study. They were divided randomly into five groups, each group with eight rats. G1: considered as a control group. G2: (1000mg/L drinking water) AlCl3. G3: (1000mg/L drinking water) AlCl3 + omega-3 oil (4000mg/kg diet). G4: (1000mg/L drinking water) AlCl3 + melatonin (50mg/kg diet). G5: (1000mg/L drinking water) AlCl3 + omega-3 oil (4000mg/kg diet) + melatonin (50mg/kg diet). All the above groups left for 40 days. The result of the biochemical study revealed a decrease in brain supernatant SOD level of AlCl3 group, while MDA level and Aβ (1-42) peptide level increased. On the other hand, melatonin, omega-3, and their combination effectively increased brain supernatant SOD level but decreased MDA and Aβ (1-42) peptide levels. AlCl3 caused many histopathological and histochemical changes in both the cerebrum and cerebellum of rats. The main histopathological features increased in the number of degenerated pyramidal neurocytes in the 3rd layer of the cerebral cortex and Purkinje cells in the cerebellum, while dietary intake of omega-3, melatonin either separately or together along with AlCl3 has the alternative effect of AlCl3. AlCl3 group showed gliosis throughout the cerebrum and cerebellum, vascular dilation and congestion, area of cytoplasmic and nuclear vacuolation, and nuclear changes, including (pyknosis, karyorhexus, and karyolysis), cerebral necrosis and edema as well as cerebellar hemorrhage. An approximately typical histological structure of the two main parts of the brain was seen in melatonin, omega-3 treated groups, as well astheir combinations. The results of the histochemical study revealed amyloid deposition in the cerebrum and cerebellum of the AlCl3 group; it was detected only in the cerebral cortex of omega-3 treated rats while not marked in melatonin and combination group. According to this study, it can be concluded that OS induced by AlCl3 caused different histopathological and histochemical changes in the cerebrum and cerebellum with many biochemical changes in brain supernatant of albino rats, while omega-3, melatonin either alone or together showed a protective role against OS of AlCl3.