Viral infection in early pregnancy is a major cause of microcephaly. However, how distinct viruses impair human brain development remains poorly understood. Here we use human brain organoids to study the mechanisms underlying microcephaly caused by Zika virus (ZIKV) and herpes simplex virus (HSV-1). We find that both viruses efficiently replicate in brain organoids and attenuate their growth by causing cell death. However, transcriptional profiling reveals that ZIKV and HSV-1 elicit distinct cellular responses and that HSV-1 uniquely impairs neuroepithelial identity. Furthermore, we demonstrate that, although both viruses fail to potently induce the type I interferon system, the organoid defects caused by their infection can be rescued by distinct type I interferons. These phenotypes are not seen in 2D cultures, highlighting the superiority of brain organoids in modeling viral infections. These results uncover virus-specific mechanisms and complex cellular immune defenses associated with virus-induced microcephaly. Display omitted •ZIKV and HSV-1 impair brain organoid growth•ZIKV and HSV-1 induce distinct morphological defects and transcriptional signatures•The two viruses differentially engage the interferon system•ZIKV and HSV-1-induced defects can be rescued by distinct interferons Krenn et al. used human brain organoids to compare the effects of ZIKV and HSV-1 on brain development. They reveal that the two viruses impair organoid growth by inducing distinct morphological and transcriptional changes. Moreover, the specific defects caused by ZIKV and HSV-1 can be prevented by distinct interferons.