Neuroinflammation can be triggered by certain nutrients. The effect of lycopene against palmitic acid-induced neuroinflammation in female rats has not been explored. This study evaluated the effects of lycopene against palmitic acid (PA)-induced neuroinflammation in rats. Twenty rats (weighing 150-200) g were randomised into six groups (n=5): Normal control, PA control, PA + lycopene (0.24 mg/kg), PA + lycopene (0.48 mg/kg), respectively. After seven weeks of PA challenge including two weeks of lycopene treatment, animals were sacrificed under Ketamine (60 mg/kg) and Xylazine (20 mg/kg), and the brain was excised for biochemical analyses. Data were analysed using one-way analysis of variance, and the means were separated with Duncan Multiple Range Test (DMRT), with P< 0.05 considered significant. The PA-induced significantly (p<0.05) increased adenosine deaminase, monoamine oxidase-A, nucleotides tri-phosphatase, 5’-nucleotidase, acetylcholine esterase, myeloperoxidase activities, and malondialdehyde level, reduced significantly post-treatment. Conversely, catalase and glutathione peroxidase activities and reduced glutathione levels decreased (in PA control) by 43%, 34%, and 12%, respectively, compared with the Normal control. Also, PA triggered a decrease in the brain phospholipids (11.43%) and cholesterol (11.11%) levels, but increased triacylglycerol level (50%). Furthermore, upregulated expressions of IL-1β, IL-6, and NF-ĸB-p65 in the PA control were attenuated, while decreased IL-10 was upregulated after treatment dose-dependently. Severe vacuolation in PA control was normalized by lycopene. This study concludes that lycopene ameliorated PA-induced neuroinflammation, probably via attenuation of oxidative stress, and downregulation of TLR4/ NF-κB -p65 axis.