DNA benefits from a system of self-maintenance, containing genes that code for the repair of its damage. The base-excision repair pathway serves as the primary means of preventing mutations attributed to oxidative stress, such as 8-oxoguanine (8-oxoG), within both the nuclear and mitochondrial DNA. Initiated by the 8-oxogunine DNA glycosylase (OGG1), the removal of 8-oxoG is known to prevent genomic instability and neoplasia. The current study presents new data indicating a role for OGG1 in the maintenance of energy homeostasis at both cellular and whole-body levels. Oxidative stress introduced via high-fat diet (HFD) yielded increased adiposity and hepatic steatosis within the OGG1 knockout (OGG1-/-) mouse model. The HFD-fed OGG1-/- mice were also prone to increased levels of plasma insulin and impaired glucose tolerance. The same mice exhibited a higher resting VCO2, indicating a preference for carbohydrate metabolism versus fat oxidation. Analysis of expression levels in the livers of OGG1-/- mice revealed significant downregulation of the metabolism-regulating transcriptional coactivator PGC1 and other genes integral to fatty acid oxidation. Consistent with a reduction in PGC1a, multiple genes involved in the TCA cycle were significantly downregulated. Also noted was a reduction in glycogen stores within the OGG1-/- livers, and fasting plasma ketones were significantly reduced. We conclude that OGG1 deficiency alters cellular substrate metabolism, fosters a fat-sparing phenotype, and renders the OGG1-/- mouse highly susceptible to obesity and related diseases. An understanding of OGG1 and its role in energy homeostasis will contribute to the direction of research within the realm of disease initiation due to oxidative stress.