Invasion and metastasis is the main causes leading to the death of hepatocellular carcinoma (HCC) patients. However, the underlying mechanism is still to be explored. Transforming growth factor β1 (TGF-β1) is a stronger inducer of HCC cell invasion. However, the downstream effector of TGF-β1 that promotes HCC invasion is still unknown. In this study, we found that PI3K/Akt activation takes place following the stimulation of TGF-β1. The inhibition of PI3K/Akt activation abolished epithelial-mesenchymal transition (EMT) and invasion of HCC cells induced by TGF-β1. Myocyte enhancer factors 2 (MEF2) family proteins were found to be overexpressed in HCC cells under the treatment of TGF-β1 in a PI3K/Akt-dependent way. Silencing the expression of MEF2s was able to prevent the effect of TGF-β1 on HCC EMT and invasion. Unexpectedly, MEF2 proteins were able to promote the expression of TGF-β1 in HCC cells, suggesting the existence of regulatory circuitry consisting of TGF-β1, PI3K/Akt, and MEF2. A natural compound, oleanolic acid, was demonstrated to suppress the invasion and EMT of HCC cells by downregulating MEF2, showing that targeting this pathway is an effective therapeutic strategy for HCC invasion. We believe that our findings can contribute to better understanding of the involved mechanism of HCC invasion and the development of preventive and therapeutic strategy.