The principal findings of this manuscript are: (1) ZIKV infection induces caspase-dependent apoptosis; (2) ZIKV infection induces three arms of ER stress; (3) Nuclear translocation of CHOP was observed in trophoblasts infected with ZIKV; and (4) Activation of JNK plays a critical role in ZIKV infection-induced trophoblast apoptosis. Here, MAPK8 is linked to Zika virus infectious disease.