Objective To improve the soluble overexpression of Newcastle disease virus(NDV) hemagylutinin-neuraminidase(HN) protein in E. Coli and determine its immunological. Methods Ten plasmids that expressed NDV HN protein with-N-terminal Grifin, gultathione-S-transferase(GST), maltose biniding protein(MBP), NusA, sanall ubiquitin-related modifier(SUMO), thioredoxin, protein G, γ-crystallin, Ars C or Ppi B tags were constructed to test the effects of the various tags on the expression level and solubility of NDV HN protein in E. coli. The sequences of the ten plasmids were confirmed and the ten plasmids were transformed into E. coli BL21 strain. In order to select and screen the best expression conditions, different induced dose isopropy-β-D-thiogalactoside(IPTG) final concentration, culture temperature, Amp final concentration and culture media were used. The expression level and solubility of fusion protein were analyzed by SDS-PAGE and Western blotting. The fusion proteins were purified by Ni-NTA chromatography to develop indirect ELISA. The purified fusion protein was detected by Western blotting and indirect ELISA. Results Ten HN fusion protein expression plasmids were constructed successfully. Maltose binding protein(MBP) tag significantly increased the HN protein soluble overexpression. The expression level was the highest. The results from Western blotting and indirect ELISA showed that the purified HN protein had a good immunogenicity. Conclusion MBP tag enhances the expression and solubility of HN protein. The study will lay foundation for the research on the NDV mechanism, vaccine and diagnostic reagents.