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The Aedes aegypti mosquito is a vector of many infectious agents, including flaviviruses such as Zika virus. Components of mosquito saliva have pleomorphic effects on the vertebrate host to enhance blood feeding, and these changes also create a favorable niche for pathogen replication and dissemination. Here, we demonstrate that human CD47, which is known to be involved in various immune processes, interacts with a 34-kilodalton mosquito salivary protein named Nest1. Nest1 is up-regulated in blood-fed female A. aegypti and facilitates Zika virus dissemination in human skin explants. Nest1 has a stronger affinity for CD47 than its natural ligand, signal regulatory protein α, competing for binding at the same interface. The interaction between Nest1 with CD47 suppresses phagocytosis by human macrophages and inhibits proinflammatory responses by white blood cells, thereby suppressing antiviral responses in the skin. This interaction elucidates how an arthropod protein alters the human response to promote arbovirus infectivity. Editor's summary: Aedes aegypti mosquitos can transmit arboviruses during blood feeding, and components of mosquito saliva may enhance both blood feeding and virus transmission. Marin-Lopez et al. identified a 34-kDa mosquito salivary protein called Nest1, highly expressed in the saliva of female A. aegypti mosquitos, as a high-affinity binder to human CD47. In human skin explants infected with Zika virus, Nest1 increased virus burden and inhibited some CD47-governed immune functions like phagocytosis and proinflammatory responses in immune cells, thus inhibiting antiviral responses. These findings provide insight into how mosquito salivary proteins can potentially facilitate arbovirus infection. —Christiana Fogg [ABSTRACT FROM AUTHOR]