Manganese is a diet-derived micronutrient that is essential for critical cellular processes like redox homeostasis, protein glycosylation, and lipid and carbohydrate metabolism. Control of Mn availability, especially at the local site of infection, is a key component of the innate immune response. Less has been elucidated about Mn homeostasis at the systemic level. In this work, we demonstrate that systemic Mn homeostasis is dynamic in response to illness in mice. This phenomenon is evidenced in male and female mice, mice of two genetic backgrounds (C57/BL6 and BALB/c), in multiple models of acute (dextran-sodium sulfate-induced) and chronic ( enterotoxigenic Bacteriodes fragilis ) colitis, and systemic infection with Candida albicans . When mice were fed a standard corn-based chow with excess Mn (100 ppm), liver Mn decreased and biliary Mn increased 3-fold in response to infection or colitis. Liver iron, copper, and zinc were unchanged. When dietary Mn was restricted to minimally adequate amounts (10ppm), baseline hepatic Mn levels decreased by approximately 60% in the liver, and upon induction of colitis, liver Mn did not decrease further, however biliary Mn still increased 20-fold. In response to acute colitis, hepatic Slc39a8 mRNA (gene encoding the Mn importer, Zip8) and Slc30a10 mRNA (gene encoding the Mn exporter, Znt10) are decreased. Zip8 protein is decreased. Illness- associated dynamic Mn homeostasis may represent a novel host immune/inflammatory response that reorganizes systemic Mn availability through differential expression of key Mn transporters with down-regulation of Zip8.