Gulf War Illness (GWI) is a chronic, progressive, multisymptom disease that affects one-third of the 700,000 U.S. military personnel deployed to 1990-1991 Gulf War. Currently, there is a paucity of available information regarding the acute and prolonged effects of GWI on synaptic plasticity and transmission. Further, GWI therapeutics are limited, leading to a demand for developing efficacious treatments for the disease. We assessed the circuit-level mechanisms underlying the detrimental acute impact of GWI-related chemicals on synaptic transmission along the hippocampal dorsoventral axis in ex vivo slice preparations. The efficacy of the immunotherapeutic lacto-N-fucopentaose-III (LNFPIII) in ameliorating GWI-specific neurological impairments in two well-established GWI animal models was also evaluated. Acute exposure to a nerve agent surrogate used in GWI animal models, diisopropylfluorophosphate (DFP), inhibited excitatory transmission via distinct cholinergic and noncholinergic mechanisms in the dH compared to the vH whereas disinhibition of inhibitory transmission in both hippocampal sectors was largely mediated by an N-methyl-D-aspartate receptor-specific mechanism. A GWI animal model comprised of pyridostigmine bromide (PB) and permethrin (PM) exposures produced long-term deficits in motor, mood, and cognitive function, acute and persisting deficits in synaptic responses along the hippocampal dorsoventral axis, and delayed neuroinflammation. Coadministration of LNFPIII during PB-PM exposure enhanced hippocampal synaptic plasticity and transmission, ameliorated PB-PM-induced deficits in dH synaptic transmission, and enhanced trophic factor expression. Delayed LNFPIII treatment beginning four months after PB-PM exposure was beneficial for behavioral responses in the motor and cognitive domains, ameliorated or enhanced hippocampal synaptic responses uniquely along the dorsoventral axis, and rebalanced neuroinflammation. In a different GWI model, an initial enhancement followed by a delayed reduction in hippocampal synaptic transmission as well as a prolonged impairment in synaptic plasticity was detected in animals exposed to N,N-diethyl-meta-toluamide, PB, DFP, and corticosterone, aberrations that became more pronounced in the dH over time. Importantly, GWI-specific synaptic abnormalities in this model were ameliorated by delayed LNFPIII treatment, ameliorations that coincided with beneficial effects on trophic factor expression in animals that received the immunotherapeutic. Collectively, these findings addressed considerable knowledge gaps in GWI research and underscore the potential for LNFPIII as an efficacious treatment for the disease state.