To shed light on the impact of systemic physiology on the pathology of traumatic brain injury (TBI), we examine the effects of TBI (concussive injury) and dietary fructose on critical aspects of lipid homeostasis in the brain and liver of young-adult rats. Lipids are integral components of brain structure and function, and the liver has a role on the synthesis and metabolism of lipids. Fructose is mainly metabolized in the liver with potential implications for brain function. Lipidomic analysis accompanied by unbiased sparse partial least squares discriminant analysis (sPLS-DA) identified lysophosphatidylcholine (LPC) and cholesterol ester (CE) as the top lipid families impacted by TBI and fructose in the hippocampus, and only LPC (16:0) was associated with hippocampal-dependent memory performance. Fructose and TBI elevated liver pro-inflammatory markers, interleukin-1α (IL-1α), Interferon-γ (IFN-γ) that correlated with hippocampal-dependent memory dysfunction, and monocyte chemoattractant protein-1 (MCP-1) positively correlated with LPC levels in the hippocampus. The effects of fructose were more pronounced in the liver, in agreement with the role of liver on fructose metabolism and suggest that fructose could exacerbate liver inflammation caused by TBI. The overall results indicate that TBI and fructose interact to influence systemic and central inflammation by engaging liver lipids. The impact of TBI and fructose diet on the periphery provides a therapeutic target to counteract the TBI pathogenesis.