DNA topoisomerases (TOPs) are dysregulated in various types of cancer. However, how TOP II-alpha (TOP2A) contributes to hepatocellular carcinoma (HCC) progression remains elusive. Cohort analysis revealed that the increased expression of TOP2A was associated with poor clinical outcomes and TOP2A was significantly upregulated in HCC tissues and cell lines. In vitro, TOP2A expression level is related to cell invasion and migration, which may be due to the alteration of epithelial-mesenchymal transition by the TOP2A. Moreover, we used verteporfin (a Hippo inhibitor) to test how the Hippo pathway promotes the effect of TOP2A on the HCC phenotype and found that TOP2A induces tumor progression through the Hippo pathway. Finally, miR-22-5p inhibited tumor progression by sponging TOP2A.