Nipah virus is an emerging, highly pathogenic, zoonotic virus of the paramyxoviridiae family. Human transmission occurs by close contact with infected animals, the consumption of contaminated food, or, occasionally, via other infected individuals. Currently, we lack therapeutic or prophylactic treatments for Nipah virus. To develop these agents we must now improve our understanding of the host-virus interactions that underpin a productive infection. This aim led us to perform the present work, in which we identified (101) human-Nipah virus protein-protein interactions (PPIs), most of which (88) are novel. This dataset provides a comprehensive view of the host complexes that are manipulated by viral proteins. Host targets include the PRP19 complex and the miRNA processing machinery. Furthermore, we explored the biologic consequences of the interaction with the PRP19 complex and found that the Nipah virus W protein is capable of altering p53 control and gene expression. We anticipate that these data will help in guiding the development of novel interventional strategies to counter this emerging viral threat.IMPORTANCE Nipah virus is recently discovered virus that infects a wide range of mammals, including humans. Since its discovery there have been yearly outbreaks and in some of them the mortality rate has reach 100% of the confirmed cases. However, the study of Nipah virus has been largely neglected and currently we lack treatments for this infection. To develop these agents we must now improve our understanding of the host-virus interactions that underpin a productive infection. In the present work we identified 101 human-Nipah virus protein-protein interactions using an affinity purification approach coupled with mass spectrometry. Additionally, we explored the cellular consequences of some of these interactions. Globally, this dataset offers a comprehensive and detailed view of the host machinery's contribution to the Nipah virus's life cycle. Furthermore, our data present a large number of putative drug targets that could be exploited for the treatment of this infection.