Hypoxia is one of the most pervasive physiological stresses within tumors. Hypoxia signaling contributes to the aggressive tumor behaviors through promoting tumor cells to undergo the fundamental metabolism adaptation. A series of evidence indicates that this process is mainly mediated by hypoxia-inducible factor (HIF). However, key molecules involved in tumor hypoxia adaptation remain to be characterized. In this study, we investigated the functional role of CD147, a transmembrane glycoprotein highly overexpressed on the surface of tumor cells, in hypoxic microenvironment using in vitro and in vivo assays. Immunohistochemical staining showed that CD147 expression was upregulated in hypoxic region of epithelial solid tumor tissues. In addition, our data indicated that hypoxia induced the upregulation of CD147 expression at both mRNA and protein levels in epithelial carcinoma cells in a time- and dose-dependent manner. Moreover, we demonstrated that hypoxia-induced CD147 upregulation was mainly mediated by a combined effect of transcription factors HIF-1 and specificity protein 1 (Sp1) on the activation of CD147 promoter. We also explored the metabolic functions of hypoxia-induced CD147 and found that upregulated CD147 promoted glycolysis in both tumor cell lines and nude mice tumor xenograft model, partially through the functional cooperation with MCT-1 and MCT-4. Finally, we observed that CD147 promoted tumor growth, inhibited tumor cell apoptosis and enhanced their invasion ability under hypoxia. In conclusion, our findings reveal a novel mechanism of hypoxia adaptation mediated by CD147 in epithelial solid tumors and suggest that CD147 may be a promising therapeutic target in cancer treatment.