The 1.6Mb 3q29 deletion (3q29Del) confers >40-fold increased risk for schizophrenia (SZ) and is also a risk factor for intellectual disability (ID) and autism spectrum disorders (ASD). No single gene in this interval is definitively associated with SZ, ID, or ASD, prompting the hypothesis that neurodevelopmental sequelae emerge upon loss of multiple functionally-connected genes. However, 3q29 interval genes are unevenly annotated and the impact of the 3q29Del on the human neural transcriptome is not known. To formulate unbiased hypotheses, we engaged a systems-level approach using the adult human cortical transcriptome to predict novel biological roles, functional inter-relations and disease associations for individual 3q29 genes. Weighted gene co-expression network analysis showed that the 21 protein-coding genes located in the 3q29 interval segregate into seven clusters, demonstrating both convergent and distributed effects across the transcriptomic landscape. Analysis of 3q29 gene-containing clusters revealed nervous-system specific functions, such as regulation and organization of synaptic signaling, as well as core aspects of cell biology, including transcriptional regulation, chromatin remodeling, protein modifications, and mitochondrial metabolism. Top network neighbors of 3q29 interval genes show significant overlap with known SZ, ASD and ID-risk genes, suggesting that 3q29Del biology is relevant to idiopathic disease. By leveraging “guilt by association”, we propose nine 3q29 genes, including one hub gene, as prioritized drivers of neuropsychiatric risk. To test these predictions, we generated the first human cellular model of 3q29Del syndrome and show that neural progenitor cell (NPC) lines derived from 3q29Del carriers empirically validate network-derived targets, highlighting both the biological relevance of this in silico analysis and this novel NPC model of 3q29Del. These results provide foundational information to formulate testable hypotheses on causal drivers and mechanisms of the largest known genetic risk factor for SZ.