Objective To evaluate the effects of matrine and artemisinin on immunocompetent hepatitis B virus (HBV) infected mouse model, and to lay a foundation for the application of the model. Methods HBV covalently closed circular DNA (HBV cccDNA) was synthesized in vitro. Male CBA/CaJ mice aged 8 to 10 weeks were injected with HBV cccDNA at high pressure through tail vein, and then intraperitoneally injected with matrine or artemisinin in acute or chronic infection periods, respectively. Quantitative PCR was used to detect HBV DNA and cccDNA in serum or liver tissues of mice. Enzyme-linked immunoadsorption assay (ELISA) was used to measure the content of HBV surface antigen (HBsAg) in serum. Immunohistochemistry was used to determine HBsAg and HBV core antigen (HBcAg) in liver tissues. Results In HBV acute infection period, matrine and artemisinin injection at week 4 significantly inhibited the secretion of HBsAg in serum of mice (both P<0.05), and reduced the expressions of HBV DNA (both P<0.01). In HBV chronic infection period, matrine and artemisinin had no significant inhibitory effects on HBsAg in serum and liver tissues (all P>0.05), but the decrease of HBsAg in serum in the group administered with matrine or artemisinin was significantly higher than that in the normal saline control group (both P<0.05). Moreover, matrine decreased the copy number of HBV DNA in serum and liver tissues (P<0.05 and P<0.01, respectively) and the copy number of HBV cccDNA in liver tissues (P<0.05). Artemisinin only inhibited the copy number of HBV DNA in serum of mice (P<0.01), but had no significant effect on HBV DNA and HBV cccDNA in liver tissues (both P>0.05). In addition, matrine had no significant effect on HBcAg in liver tissues (P>0.05), but artemisinin did the opposite (P<0.05). Conclusion The immunocompetent HBV cccDNA mouse model can be used to evaluate the efficacy of drugs for the treatment of acute and chronic hepatitis B.