Cytomegalovirus (CMV) is a ubiquitous β-herpes virus with seroprevalence rates upwards of 80% in some populations. An obligate parasite, CMV alters the host cell’s metabolic pathways to produce the biomaterials and energy necessary for successful viral replication. While congenital infections and those occurring in immunocompromised populations can have serious consequences, for the majority of the population the virus has been regarded as benign. Accumulating evidence has implicated CMV in unhealthy aging and the development of age associated diseases such as cancer (such as glioblastoma (GB)) and dementia. We hypothesized that CMV may function in an oncomodulatory capacity providing some survival or proliferative benefit to the cancer. Following infection of GB cells with CMV we determined that infection enhanced both the glycolytic and oxidative phosphorylation pathways resulting in an increased production of lactate and reactive oxygen species. We also demonstrated that, independent of viral transmission, infected cells were able to alter the metabolism and epigenetic landscape of neighboring cells. These findings suggest that CMV infected cells possess a remarkable ability to manipulate the tumor microenvironment in a manner which may provide metabolic flexibility to the tumor. Following these in vitro results we examined the effect of periodic CMV reactivation had on a murine model of aging. We discovered that CMV infection produces a systemic inflammatory response and delayed neuroinflammation. Moreover, there was significant metabolic reprogramming and oxidative stress indicative of mitochondrial dysfunction in brain microvascular endothelial cells (BMECs). To understand the physical manifestations of the collective metabolic and functional changes observed in our mouse model, we completed a series of cognitive assays and identified clear cognitive impairment in spatial working memory at 12 months post infection. Taken together, our data indicates that periodic CMV exposure alters metabolic pathways in the BBB and accelerates cognitive decline. These results were observed at “middle age” in mice, a time in which human correlates would still be in the symptomless phase of cognitive decline. Our work demonstrates a mechanistic relation between pathogen exposure and cognitive decline or dementia related pathologies. This research highlights metabolic dysfunction and oxidative stress as potential therapeutic targets to mitigate the impact of pathogen exposure on unhealthy aging. Findings from this research may enable future generations to experience enhanced quality of life at advanced age.