Objective To establish a mouse model of liver cancer by injecting mutant p53 gene CRISPR/ Cas9 plasmid and H22 cells into the tail vein. Methods Healthy male BALB/ c mice were randomly divided into blank group (normal saline), plasmid group ( Plasmid), control group ( H22 cells + saline) and experimental group ( H22 cells + Plasmid), each with 25 mice. Tail vein injection was used to establish the liver cancer model. Samples were taken at 2, 3, 4 and 5 weeks after the injection, and blood was collected from the orbit to detect serum aminotransferase (ALT/ AST). Liver and lung surface changes and the number of nodules were observed, and successful modeling rate, mortality and organ index in each group were assessed. HE staining was used to observe the pathological and morphological changes in the liver. Immunohistochemistry, western blot and other method were used to evaluate the expression of p53 and PCNA protein in the liver. Results Both the experimental group and the control group showed successful generation of a mouse model of metastatic liver cancer. The rates of successful modeling in the experimental and control groups were 60. 87% and 45. 83%, respectively, and the mortality rate was 4. 35% and 29. 17%, respectively. The serum ALT and AST levels in the two groups of mice increased significantly, and cysts and white granular nodules of varying sizes appeared on the liver surface over time. The HE result showed that the liver lobules in the experimental and control groups were damaged to varying degrees after 5 weeks, showing obvious tumor-related pathological changes. The expression of p53 protein in the liver of the plasmid and experimental groups was significantly reduced (P< 0. 05). The expression of PCNA protein in the liver tissue of the experimental and control groups was increased significantly, and expression was significantly higher in the experimental group compared with the control group (P< 0. 05). Conclusions The method of injecting mutant p53 gene CRISPR/ Cas9 plasmid and H22 cells through the tail vein can successfully and rapidly construct a mouse model of metastatic liver cancer.