Objective To optimize the best dosage and proportion of each component of Qizhu Capsule in the prevention of CCl4 induced acute liver injury in mice. Methods The CCl4 induced acute chemical liver injury model in mice was established. Alanine aminotransferase(ALT) and aspartate aminotransferase(AST) in serum were detected and used as pharmacodynamic evaluation indexes. The experimental design of multi factor compatibility of total saponin of Aralia elata, total flavonoid of Begonia hupehensis and total polyphenol of Phyllanthus were carried out by using the central composite design-response surface methodology. The experimental results were fitted by multiple regression, and more than two items were obtained according to the binomial fitting equation, the three-dimensional effect surface map of the influence trend of factors on the index was drawn, and the best dosage and compatibility ratio of each component of Qizhu Capsule were screened. Results During the experiment, the mice in each group had good diet and activity, no adverse reactions and no death. The best compatibility of Qizhu Capsule was 0.05 g/kg total saponins of Aralia taibaiensis, 0.84 g/kg total flavonoids of Begonia hupehensis and 1.25 g/kg total polyphenols of Phyllanthus. Conclusion Central composite design-response surface methodology could applied to optimize the compatibility conditions of Qizhu Capsule. This method is simple and predictive, which may provide an effective scientific basis for its clinical application.