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Metabolic programming of cancer cells is an essential step in transformation and tumor growth. We established two‐dimensional (2D) monolayer and three‐dimensional (3D) cultures, the latter called a "tissueoid cell culture system", using four types of tongue cancer cell lines. We also undertook a comprehensive metabolome analysis of three groups that included xenografts created by transplanting the cell lines into nude mice. In addition, we undertook a functional analysis of the mitochondria, which plays a key role in cancer metabolism. Principal component analysis revealed the plots of the four cell lines to be much narrower in 2D culture than in 3D culture and xenograft groups. Moreover, compared to xenografts, the 2D culture had significantly lower levels of most metabolites. These results suggest that the unique characteristics of each cell disappeared in 2D culture, and a type of metabolism unique to monolayer culture took over. Conversely, ATP production, biomass synthesis, and maintenance of redox balance were shown in 3D culture using sufficient nutrients, which closely resembled the metabolic activity in the xenografts. However, there were several differences between the metabolic activity in the 3D culture and xenografts. In vivo, the cancer tissue had blood flow with stromal cells present around the cancer cells. In the xenografts, we detected metabolized and degraded products in the liver and other organs of the host mice. Furthermore, the 3D system did not show impairment of mitochondrial function in the cancer cells, suggesting that cancer cells produce energy simultaneously through mitochondria, as well as aerobic glycolysis. [ABSTRACT FROM AUTHOR]