We provide evidence that ZIKV infection may trigger intracellular Ca2+ increases to promote TRPC4 expression via the activation of CaMKII–CREB, TRPC4-mediated Ca2+ influx in turn increases nuclear translocation of DDX3X, a critical step during ZIKV replication, and ZIKV-NS3 potentiates TRPC4 protein expression and function, further stimulating ZIKV replication. This evidence concerns the gene TRPC4 and Zika virus infectious disease.