Recent findings from our lab have shown that peripheral infection of adult mice with influenza A/PR/8/34 (H1N1) virus induces a neuroinflammatory response that is paralleled by loss of neurotrophic and glial regulatory factors in the hippocampus, and deficits in cognitive function. Environmental enrichment has been shown to exert beneficial effects on the brain and behavior in many central nervous system (CNS) disorders, but its therapeutic potential during peripheral viral infection remains unknown. Therefore, the objective of the present study was to determine if long-term continuous exposure to environmental enrichment could prevent and/or attenuate the negative effects of influenza infection on the hippocampus and spatial cognition. Mice were housed in enriched or standard conditions for 4months, and continued to live in their respective environments throughout influenza infection. Cognitive function was assessed in a reversal learning version of the Morris water maze, and changes in hippocampal expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-α), neurotrophic (BDNF, NGF), and immunomodulatory (CD200, CX3CL1) factors were determined. We found that environmental enrichment reduced neuroinflammation and helped prevent the influenza-induced reduction in hippocampal CD200. These changes were paralleled by improved cognitive performance of enriched mice infected with influenza when compared to infected mice in standard housing conditions. Collectively, these data are the first to demonstrate the positive impact of environmental enrichment on the brain and cognition during peripheral viral infection, and suggest that enhanced modulation of the neuroimmune response may underlie these beneficial effects.