Monosodium glutamate (MSG) has a long history of use enhancer to flavor food but modern scientific research has shown that it has very serious damage to the different organs of the body, especially the nervous system. Aspartame (ASP) is one of the most widely used artificial sweeteners in the world. ASP was assured to induce many hazardous effects on the structure and functions of the brain. Opuntia ficus indica fruit as a source of natural liquid sweetener cactus fruit juice laden with total phenolic, total flavonoids, vitamin C, vitamin E, and β-carotene can safeguard the body against oxidative stress and minimize cataract risk in diabetes patients. This work aims to evaluate the possible ameliorative role of fruit juice of O. ficus indica against MSG and ASP-induced cerebellar toxicity in female rats and their fetuses.   For this study, 36 pregnant females were used in this study and randomly divided into six groups on the fourth day of gestation: control, Opuntia group, MSG group, ASP group, MSG plus O. ficus indica group, and ASP plus O. ficus indica group. The experiment extended from the fourth day of pregnancy till the end of weaning. At the end of the experiment, the mother's rats and their pups were dissected for collection of blood and removal of the cerebellum for estimation of biochemical and histopathological changes.  The obtained results revealed pronounced histopathological signs in the cerebellar cortex of MSG, and ASP-treated dams and their pups. These signs included disorganized cerebellar layers, pyknotic Purkinje and granular cells, and scattered vacuoles. The immunohistochemical results revealed strong expression for GFAP and P53 protein while weak expression for Bcl-2 in the cerebellar cortex of MSG and ASP groups compared with control. Additionally, the obtained biochemical analysis shows a significant increase in the levels of caspase-3 and IL-1 in the cerebellar tissue while a significant decrease in the levels of serum insulin and IGF-1 compared with control. Co-supplementation of O. ficus indica fruit juice with MSG or ASP successfully alleviated the deleterious histopathological, immunohistochemical, and biochemical changes induced by MSG and ASP.