Several systems-level datasets designed to dissect host-pathogen interactions during influenza A infection have been reported. However, apparent discordance among these data has hampered their full utility toward advancing mechanistic and therapeutic knowledge. To collectively reconcile these datasets, we performed a meta-analysis of data from eight published RNAi screens and integrated these data with three protein interaction datasets, including one generated within the context of this study. Further integration of these data with global virus-host interaction analyses revealed a functionally validated biochemical landscape of the influenza-host interface, which can be queried through a simplified and customizable web portal (http://www.metascape.org/IAV). Follow-up studies revealed that the putative ubiquitin ligase UBR4 associates with the viral M2 protein and promotes apical transport of viral proteins. Taken together, the integrative analysis of influenza OMICs datasets illuminates a viral-host network of high-confidence human proteins that are essential for influenza A virus replication. Display omitted •Meta-analysis of influenza OMICs datasets reveals high-confidence virus-host interactions•Integration of orthogonal data exposes unique host and restriction factor activities•Experimental validation of virus-host circuits supports robustness of approach•The host E3 ligase UBR4 is identified as essential for virus budding and pathogenesis Tripathi et al. have reconciled and integrated divergent influenza “OMICs” studies to reveal a functionally validated virus-host interaction network of high-confidence human proteins essential for influenza A virus replication. The authors leverage this approach to identify UBR4 as a host protein essential for virus budding and pathogenesis.