Manganese is considered essential for animal growth. Manganese ions serve as cofactors to three mitochondrial enzymes: superoxide dismutase (Sod2), arginase and glutamine synthase. In Drosophila melanogaster, manganese has also been implicated in the formation of ceramide phosphoethanolamine, the insect’s sphingomyelin analogue, a structural component of membranes. Manganese overload leads to neurodegeneration and toxicity in both humans and Drosophila. Here, we describe a Drosophila model of manganese deficiency. Due to the lack of manganese-specific chelators, we used chemically defined media to grow the flies and deplete them of the metal. Dietary manganese depletion reduces Sod2 activity. We then examined gene and protein expression changes in the intestines of manganese depleted flies. We found adaptive responses to the lack of the known manganese-dependent enzymatic activities and alterations in genes/enzymes of carbohydrate metabolism and glycosylations, similar to earlier reports of manganese deficiency in vertebrate animals.