Background and Objectives: Children consume fast food rich in saturated fats and flavor enhancers like Monosodium Glutamate (MSG). These agents might alter Hypothalamic-Pituitary Adrenal (HPA) axis activity, inducing behavioral deficits. Consequently, we hypothesized that adding saturated fat to MSG-treated rats' diet could exaggerate their HPA axis response, behavioral deficits and systemic inflammation whereas dietary polyunsaturated omega-3 fatty acids could alleviate MSG-induced detrimental effects by affecting hypothalamic Glucocorticoid Receptor (GR) and microRNAs. Materials and Methods: To test current hypotheses, young male rats were gavaged with 3 g/kg MSG and concurrently fed either a normal or a 10% palm oil- or a 10% fish oil-enriched diet for 4 months. Results: Feeding saturated fats to MSG-treated rats aggravated HPA axis activation and hypothalamic GR down-regulation. They also worsened MSG-triggered cognitive impairment and depressive-like behavior. Saturated fats also amplified systemic inflammation by up-regulating hypothalamic Nuclear Factor kappa B (NFkB) and Toll-Like Receptor 4 (TLR4). Conversely, dietary omega-3 fatty acids significantly alleviated MSG-induced HPA axis activation and hypothalamic microRNA218 (miRNA218) up-regulation. Additionally, these fatty acids markedly ameliorated GR down-regulation. They also protected MSG-treated rats against cognitive dysfunction, depressive-like behavior and systemic inflammatory responses. Their anti-inflammatory potential was coupled with down-regulation of NFkB and TLR4 and up-regulation of miRNA155 in the hypothalamus. Conclusion: Thus, it is highly recommended to replace saturated with omega-3 fatty acids in fast foods to prevent MSG harmful effects on the HPA axis, particularly in children, after performing broad-scale clinical trials