Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are closely related to mosquito-borne flaviviruses. Japanese encephalitis (JE) vaccine SA14-14-2 has been in the Chinese national Expanded Program on Immunization since 2007. The recent recognition of severe disease syndromes associated with ZIKV, and the identification of ZIKV from mosquitoes in China, prompts an urgent need to investigate the potential interaction between the two. In this study, we showed that SA14-14-2 is protective against ZIKV infection in mice. JE vaccine SA14-14-2 triggered both Th1 and Th2 cross-reactive immune responses to ZIKV; however, it was cellular immunity that predominantly mediated cross-protection against ZIKV infection. Passive transfer of immune sera did not result in significant cross-protection but did mediate antibody-dependent enhancement in vitro, though this did not have an adverse impact on survival. This study suggests that the SA14-14-2 vaccine can protect against ZIKV through a cross-reactive T cell response. This is vital information in terms of ZIKV prevention or precaution in those ZIKV-affected regions where JEV circulates or SA14-14-2 is in widespread use, and opens a promising avenue to develop a novel bivalent vaccine against both ZIKV and JEV.