Correlational studies have linked pathogenic infections, including those induced by lipopolysaccharide (LPS), with learning and/or memory impairments, as opposed to beneficial roles of IL-4 on hippocampal-mediated cognitive performance. However, there is still paucity of information regarding the exact domain of cognition affected by systemic LPS exposure with reference to endogenous secretions and signalling of bioactive immune modulators (TNF-α versus IL-4). This study was aimed at investigating the neurotoxic effects of LPS on hippocampal-mediated cognitive functions, assessed through critical evaluation of spatial learning and reference memory tasks in the Morris water maze (MWM), with reference to synaptic plasticity and perturbed neuro-immune responses. Thirty-six BALB/c mice (18-20g) were randomly divided into six groups (n=6/group) which received i.p injections of sterile saline or 5mg/kg E.coli lipopolysaccharide (LPS), aspirin (100mg/kg) or cyanocobalamin (1000mcg/kg) by gavage, while others received combined treatments of either LPS/aspirin or LPS/cyanocobalamin. 48h post LPS challenge, mice were pre-treated with either aspirin or cyanocobalamin one hour before the swimming sessions in MWM. Thereafter, mice were anaesthetized, and blood was collected via cardiac puncture. The brains were removed using appropriate forceps, while the hippocampi were dissected out on ice cold surface and immediately processed for molecular assessment of TNF-α and IL-4 by ELISA. Whole brains were also preserved in neutral buffer formalin for subsequent morphological analysis by H&E staining and expression of hippocampal Nissl bodies using cresyl violet stain. Our data showed that systemic LPS injection significantly increased the latency to platform crossings during acquisition phase of MWM task without any significant change during the probe test. These changes were accompanied by elevated TNF-α and decreased BDNF levels in the hippocampi of LPS treated mice compared to control. This suggest a decrease in memory consolidation due to neurotoxic effect of LPS. Surprisingly, cyanocobalamin treatment appears to have neurotoxic effects when given at a moderate dose of 1000mcg/kg. Conversely, hippocampal IL-4 was not significantly different among all the treated groups. Also, LPS-induced morphological changes was partly reversed while moderate expression of nissil bodies was associated with LPS treatment. This study underlines the impact of systemic LPS challenge on modulation of endogenous hippocampal molecules with severe consequences on learning components of cognition.