It has been reported worldwide that the Zika virus (ZIKV) could be transmitted through placentas and sexual contact. ZIKV can also cause Guillain-Barre syndrome, microcephaly and neurological abnormalities. However, there are no approved vaccines available. We constructed six DNA vaccine candidates and tested the immunogenicity. Tandem repeated envelope domain Ⅲ (ED Ⅲ × 3) induced highly total IgG and neutralization antibody, as well as CD8+ T cell responses. Also, stem region-removed envelope (E ΔSTEM) elicited a robust production of IFN-γ in mice. To examine in vivo protection, we used mice treated with an IFNAR1 blocking antibody before and after the challenge. Vaccination with the two candidates led to a decline in the level of viral RNAs in organs. Moreover, the sera from the vaccinated mice did not enhance the infection of Dengue virus in K562 cells. These findings suggest the potential for the development of a novel ZIKV DNA vaccine. •We constructed the 6 DNA vaccine candidates using envelope (E) protein of Zika virus.•Domain III tandem repeated (ED III × 3) and stem region-removed (E ΔSTEM) E protein were selected as effective vaccine candidates.•ED Ⅲ × 3 DNA immunization induced an efficient neutralization antibody and CD8+ T cell responses in a mouse model.•E ΔSTEM DNA immunized mice showed a robust production of IFN-γ and an efficacious protection against the Zika virus.