Maternal high-fat diet (mHFD) during pregnancy leads to increased inflammation and oxidative stress, representing an important risk factor for fetal neurodevelopment. We have previously shown, in a mouse model of mHFD, sex-dimorphic negative outcomes in the adolescent offspring, disrupting hippocampal Bdnf-Nrf-2 crosstalk specifically in females. In this study, we hypothesize that sex-differences are still present during adulthood, affecting cognition and neurotransmission. Furthermore, we tested a maternal dietary supplementation with the antioxidant N-acetyl-cysteine (NAC) as a preventive strategy.Female C57BL/6N mice were fed either HFD or CD before and during pregnancy (13 weeks). After 5 weeks on diets, they received NAC (1g/kg) until delivery. Cognitive function was assessed in adult male and female offspring through the Morris Water Maze (MWM). HPA axis functionality following acute stress was assessed by plasma corticosterone measurements by ELISA. Gene expression of Vglut1 and Vgat was assessed by RealTime PCR.Exposure to mHFD reduced hippocampal markers of inhibitory synapses (Vgat1), disrupting Vglut1/Vgat balance towards excessive excitatory input, in both sexes. Interestingly, selectively in female offspring, we observed impaired memory retention in the MWM and increased HPA reactivity in response to an acute stress. Prenatal supplementation with NAC improved cognitive abilities by restoring Vglut1/Vgat balance.Overall, data show that mHFD has permanent negative effects on offspring neurodevelopment, with more severe effects in female adult offspring, leading to E/I neuronal imbalance with concomitant disruptions of cognitive abilities and neuroendocrine reactivity. The rescue of NAC confirms a pivotal role of oxidative stress in mediating the long-term effects of mHFD.