Sodium valproate combined with decitabine can inhibit cancer by inhibiting the invasion and metastasis of liver cancer cells of which the mechanism is not yet clear. In this study, valproic acid and decitabine were used during the culture of liver cancer cell that is human hepatocarcinoma cell line SMMC-7721 and the p38 mitogen-activated protein kinase activator anisomycin was added. Western blot was used to detect the expression of E-cadherin and vimentin proteins. Transwell experiment was used to detect the migration and invasion ability of liver cancer cells. Quantitative reverse transcription polymerase chain reaction and western blot were used to detect p38 mitogen-activated protein kinase/heat shock protein 27 signaling pathway expression changes and p53 expression levels. The results show that the combination of valproic acid and decitabine can significantly reduce the invasion and metastasis ability of SMMC-7721 cells and the expression of vimentin protein, occurrence of epithelial-mesenchymal transition and p38 mitogen-activated protein kinase/phospho-p38 mitogen-activated protein kinase/heat shock protein 27/phospho heat shock protein 27. At the same time, it increases the expression of E-cadherin protein and the expression level of p53 (p<0.05) and the p38 mitogen-activated protein kinase activator anisomycin can inhibit the mentioned effects. These data show that the inhibition of epithelial-mesenchymal transition and invasion and metastasis of liver cancer cells may be achieved by increasing the expression of p53 which is through inhibiting the expression of p38 mitogen-activated protein kinase/heat shock protein 27 and its phosphorylation level when valproic acid and decitabine is combined.