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Summary To gain insight into the cellular and molecular cues that promote neurovascular co-patterning at the earliest stages of human embryogenesis, we developed a human embryonic stem cell model to mimic the developing epiblast. Contact of ectoderm-derived neural cells with mesoderm-derived vasculature is initiated via the neural crest (NC), not the neural tube (NT). Neurovascular co-patterning then ensues with specification of NC toward an autonomic fate requiring vascular endothelial cell (EC)-secreted nitric oxide (NO) and direct contact with vascular smooth muscle cells (VSMCs) via T-cadherin-mediated homotypic interactions. Once a neurovascular template has been established, NT-derived central neurons then align themselves with the vasculature. Our findings reveal that, in early human development, the autonomic nervous system forms in response to distinct molecular cues from VSMCs and ECs, providing a model for how other developing lineages might coordinate their co-patterning., Graphical Abstract, Highlights • Neural crest (NC) cells drive neurovascular co-patterning, as modeled by hESC • Autonomic differentiation of NC cells depends on contact with perivascular cells • This requires endothelial-derived NO and T-cadherin-mediated interaction with VSMCs, Cheresh, Snyder, and colleagues demonstrate how direct contact between hESC-derived neural crest (NC) cells and the vasculature promotes autonomic differentiation. In a hESC model mimicking the developing epiblast, NC cells initiate neurovascular co-patterning prior to forming neural tube neurons. Endothelial-secreted NO and direct contact with vascular smooth muscle cells via T-cadherin are required to promote NC differentiation into autonomic neurons.