Despite the rapidly identified numbers of lncRNA in humans, exploration of the molecular mechanisms of lncRNA is lagging, because the molecular mechanisms of lncRNA can be various and complex in different conditions. In this study, we found a new molecular mechanism for a versatile molecule, MIR22HG. MIR22HG is an lncRNA that contributes to the initiation and progression of many human cancers, including hepatocellular carcinoma (HCC). We report that MIR22HG was downregulated in 120 HCC samples compared with adjacent nontumor liver tissues. More interestingly, decreased expression of MIR22HG in HCC could predict poor prognosis of HCC patients. Knockdown of MIR22HG promoted the growth, migration and invasion of HCC cells. In exploring the molecular mechanism of MIR22HG, we found that MIR22HG functioned as a tumor suppressor in hepatocellular carcinomas, in part through serving as a competing endogenous RNA to modulate the miRNA‐10a‐5p level. Moreover, NCOR2 was verified to act as the downstream target gene of MIR22HG/miR‐10a‐5p. In addition, the MIR22HG/miRNA‐10a‐5p/NCOR2 axis inhibited the activation of the Wnt/β‐catenin pathway. Together, our results demonstrated that MIR22HG inhibited HCC progression in part through the miR‐10a‐5p/NCOR2 signaling axis and might act as a new prognostic biomarker for HCC patients. A schematic model depicting the molecular mechanism of MIR22HG in hepatocellular carcinoma.