We have previously found that healthy aged rats are more likely to suffer profound memory impairments following a severe bacterial infection than are younger adult rats. Such a peripheral challenge is capable of producing a neuroinflammatory response, and in the aged brain this response is exaggerated and prolonged. Normal aging primes, or sensitizes, microglia, and this appears to be the source of this amplified inflammatory response. Among the outcomes of this exaggerated neuroinflammatory response are impairments in synaptic plasticity and reductions of brain-derived neurotrophic factor (BDNF), both of which have been associated with cognitive impairments. Since it has been shown that physical exercise increases BDNF mRNA in the hippocampus, the present study examined voluntary exercise in 24-month-old F344×BN rats as a neuroprotective therapeutic in our bacterial infection model. Although aged rats ran only an average of 0.7 km per week, this small amount of exercise was sufficient to completely reverse infection-induced impairments in hippocampus-dependent long-term memory compared with sedentary animals. Strikingly, exercise prevented the infection-induced exaggerated neuroinflammatory response and the blunted BDNF mRNA induction seen in the hippocampus of sedentary rats. Moreover, voluntary exercise abrogated age-related microglial sensitization, suggesting a possible mechanism for exercise-induced neuroprotection in aging.