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Summary The complex 16p11.2 deletion syndrome (16pdel) is accompanied by neurological disorders, including epilepsy, autism spectrum disorder, and intellectual disability. We demonstrated that 16pdel iPSC differentiated neurons from affected people show augmented local field potential activity and altered ceramide-related lipid species relative to unaffected. FAM57B, a poorly characterized gene in the 16p11.2 interval, has emerged as a candidate tied to symptomatology. We found that FAM57B modulates ceramide synthase (CerS) activity, but is not a CerS per se. In FAM57B mutant human neuronal cells and zebrafish brain, composition and levels of sphingolipids and glycerolipids associated with cellular membranes are disrupted. Consistently, we observed aberrant plasma membrane architecture and synaptic protein mislocalization, which were accompanied by depressed brain and behavioral activity. Together, these results suggest that haploinsufficiency of FAM57B contributes to changes in neuronal activity and function in 16pdel syndrome through a crucial role for the gene in lipid metabolism., Graphical abstract, Highlights • Augmented LFP activity and sex-specific differences in 16pdel neurons • 16pdel neuronal lipidome indicated altered ceramide related species • FAM57B is a ceramide synthase modulator essential for lipid regulation in the brain • FAM57B functions in synaptogenesis, synapse architecture, and composition, Cellular neuroscience; Developmental neuroscience; Molecular neuroscience; Neuroscience