The present study investigated if treatment with the immunotherapeutic, lacto-N-fucopentaose-III (LNFPIII), resulted in amelioration of acute and persisting deficits in synaptic plasticity and transmission as well as trophic factor expression along the hippocampal dorsoventral axis in a mouse model of Gulf War Illness (GWI). Mice received either coadministered or delayed LNFPIII treatment throughout or following, respectively, exposure to a 15-day GWI induction paradigm. Subsets of animals were subsequently sacrificed 48 h, seven months, or 11 months post GWI-related (GWIR) exposure for hippocampal qPCR or in vitro electrophysiology experiments. Progressively worsened impairments in hippocampal synaptic plasticity, as well as a biphasic effect on hippocampal synaptic transmission, were detected in GWIR-exposed animals. Dorsoventral-specific impairments in hippocampal synaptic responses became more pronounced over time, particularly in the dorsal hippocampus. Notably, delayed LNFPIII treatment ameliorated GWI-related aberrations in hippocampal synaptic plasticity and transmission seven and 11 months post-exposure, an effect that was consistent with enhanced hippocampal trophic factor expression and absence of increased interleukin 6 (IL-6) in animals treated with LNFPIII. Approximately a third of Gulf War Veterans have GWI; however, GWI therapeutics are presently limited to targeted and symptomatic treatments. As increasing evidence underscores the substantial role of persisting neuroimmune dysfunction in GWI, efficacious neuroactive immunotherapeutics hold substantial promise in yielding GWI remission. The findings in the present report indicate that LNFPIII may be an efficacious candidate for ameliorating persisting neurological abnormalities presented in GWI. •GWI-related exposures induced a biphasic effect on basal synaptic transmission.•Progressively worsened impairments in hippocampal LTP were found in GWI animals.•Synaptic deficits were more pronounced in the dH than the vH in GWI animals.•Coadministered LNFPIII enhanced synaptic plasticity and transmission.•Delayed LNFPIII treatment ameliorated GWI deficits 11 months post-exposure.