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Here, we investigated the protein network regulating cholesterol metabolism in the liver and brain of adolescent and adult male and female rats prenatally exposed to valproate (VPA), a well validated experimental model of autism spectrum disorders (ASD). We were aimed at studying whether prenatal VPA exposure affected the proteins involved in cholesterol homeostasis in a sex‐dependent manner. To this aim the protein network of cholesterol metabolism, in term of synthesis and plasma membrane trafficking, was analyzed by western blot in the liver and different brain areas (amygdala, cerebellum, cortex, hippocampus, nucleus accumbens, and dorsal striatum) of adolescent and adult male and female rats prenatally exposed to VPA. Our results show that physiological sex‐dependent differences are present both in the liver and in brain of rats. Interestingly, VPA affects specifically the brain in an age‐ and region‐specific manner; indeed, cerebellum, cortex, hippocampus and nucleus accumbens are affected in a sex‐dependent way, while this does not occur in amygdala and dorsal striatum. Overall, we demonstrate that each brain area responds differently to the same external stimulus and males and females respond in a different way, suggesting that this could be related to the diverse incidences, between the sexes, of some neurodevelopmental pathologies such as autism, which displays a 3:1 male to female ratio. Prenatal exposure to valproate (VPA) induces cholesterol metabolism alteration in brain. VPA‐induced cholesterol metabolism alterations are dimorphic and dependent on age. VPA‐induced cholesterol metabolism alterations could be related to autism spectrum disorder (ASD). [ABSTRACT FROM AUTHOR]