Objective：This study amis to prepare the genetically engineered human-mouse chimeric antibody against hepatitis E virus（HEV）and investigate its protective neutralization and properties. Methods：To optimize the obtained anti-HEV murine monoclonal antibody gene sequence，the human-mouse chimeric engineered antibody gene sequences were designed and cloned into the antibody eukaryotic expression vectors；vectors were co-transfected into 293F cells for optimal expression，and the genetically engineered antibody was efficiently prepared. The binding ability and neutralizing activity of the engineered antibody was studied by enzyme linked immunosorbent assay（ELISA），immunofluorescence and HEV cell infection model. Results：The engineered human-mouse chimeric HEV protective antibody expression vectors were constructed successfully，and the engineered human-mouse chimeric HEV protective antibody was expressed in the 293F expression system efficiently. Antibody expression yield reached 30 mg/L，binding affinity of the antibody was 1.202×10-8 mol/L. Immunofluorescence results showed that the antibody could sensitively and specifically bind to Kernow cells infected by HEV. The results of quantitative real-time PCR showed that the antibody could protect susceptible C3A cells from HEV infection. Conclusion：Gene engineering antibody has high HEV binding capacity and efficient neutralization protection，which can effectively block HEV infection and be achieved with low-cost and high-efficiency.