Malignant glioma is the most common type of human intracranial cancer and has poor prognosis due to its high recurrence and invasiveness. However, the molecular mechanisms underlying its malignant phenotypes have still not been completely explored yet. miR-122 has been well documented to act as a tumor suppressor for hepatocellular carcinoma and breast cancer, but the implication of miR-122 in the progression of glioma is not clear yet. In this study, we found that miR-122 was underexpressed in glioma specimens and glioma cell lines, compared with normal brain tissues and cell lines. The expression of miR-122 levels is inversely correlated with the survival of patients after surgery. Overexpression of miR-122 by an adenoviral vector suppressed the proliferation and colony formation of glioma cells. The in vivo tumorigenicity of U-87 MG cells was also greatly compromised by restoring miR-122. miR-122 suppressed the activation of Wnt/β-catenin pathway in glioma cells. Interestingly, Wnt/β-catenin signaling conversely reduced the expression of miR-122 in glioma cells, maybe in a hepatocyte nuclear factor (HNF)-dependent mechanism. Taken together, we revealed that there is a miR-122/Wnt/β-catenin regulatory circuitry existing in glioma cells that contributes to glioma progression.