Flaviviruses are enveloped positive-strand RNA viruses of the family Flaviviridae, are emerging as a significant global human health threat. Flaviviruses such as Zika virus remodel intra-cellular lipid membranes to form replication factories. How ZIKV regulates lipid networks to allow infection, and consequences for the disease is poorly understood. To determine how Zika virus modulates the host lipid repertoire in an unbiased manner, we performed detailed lipid profiling of cells infected with the virus. We then used a combination of CRISPR/Cas9 genome editing, pharmacological inhibitors, and lipid probes to interrogate the key lipid pathways that are differentially regulated upon infection. We found that Zika virus remodels multiple aspects of human lipid metabolism, with species of sphingomyelin and ceramide most highly enriched during infection. Zika virus is known to cause microcephaly by infecting the developing brain, one of the most lipid-rich tissues in the body. Although the exact causes of this neurotropism and virulence are unknown, the brain's lipid microenvironment may have a role in this process. Our finding supports this hypothesis and provides new conceptual insight into Zika virus biology and pathogenesis.