The innate immune receptor Toll-like-Receptor 3 TLR3) was up regulated after zikv infection of human organoids and mouse neurospheres and TLR3 inhibition reduced the phenotypic effects of ZIKV infection. Pathway analysis expression changes during TLR3 activation highlighted 41 genes also related to neuronal development, suggesting a mechanistic connection to disrupted neurogenesis. Together, therefore, our findings identify a link between ZIKV-mediated TLR3 activation, perturbed cellfate, and a reduction in organoid volume reminiscent of microcephaly