Regular aerobic endurance exercise has been considered to have neuroprotective effects, with recent evidence suggesting its potential role in modulating inflammatory mediators and microglia states and functions in the central nervous system. Most of the published data to date have been generated using male mice, hence the effects of both exercise and experimentally-induced neuroinflammation are less well-investigated, and hence are less well-understood in female mice.Here, we investigated the impact of 7 consecutive days of low-to-moderate-intensity treadmill running on microglial activation in 3-month-old female and male C57BL/6J mice who were subsequently subjected to an induced peripheral immune challenge via subseptic dose of lipopolysaccharide (LPS). Furthermore, we assessed the spatial memory of the mice using the Novel Object Location task. We also assessed the bioenergetic phenotype of primary microglia in both exercising and non-exercising mice.Our findings indicate that the effects of both exercise and the response to the induced immune challenge by LPS are sex-specific. Prior exercise in males rescued their spatial memory after systemic inflammation, whereas in females, spatial memory was not affected independent of prior exercise or LPS challenge. Cytokine expression from hippocampal tissue and serum also differed significantly between sexes, with the female mice appearing to be more resistant to the effects of experimentally-induced inflammation.Altogether, these results suggest that male and female mice respond differently to both LPS challenge and exercise, reinforcing the need to further delve into the underlying molecular mechanisms associated with the observed effects and the potential translational impact of these data.