["Autism Research, EarlyView. ", "\nABSTRACT\nAutism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, abnormal social interactions, and restricted, repetitive behaviors. Pathogenic mutations in UBE3B result in neurodevelopmental disease, including intellectual disability, lack of speech, and ASD. UBE3B is an E3 ubiquitin ligase that tags substrate proteins with ubiquitin, marking them for proteasomal degradation. The ubiquitin‐proteasome system (UPS) regulates several signaling pathways critical for neurodevelopment, including neurogenesis and synaptogenesis, and mutations in various UPS genes have been identified in ASD and related neurodevelopmental disorders. To investigate the function of UBE3B in the brain and how its disruption gives rise to neurodevelopmental abnormalities, we generated a central nervous system‐specific conditional Ube3b knockout (cKO) mouse model and evaluated the resulting neurobehavioral phenotypes. We found that Ube3b cKO mice exhibit severe deficits in vocalization, social behavior, learning and memory, and motor skills. Assessment of in vivo neuronal phenotypes revealed defects in dendritic morphogenesis, reduced excitatory synapse density, diminished spontaneous cortical circuit activity, decreased AMPA receptor surface expression, and hyperexcitability of excitatory cortical neurons. Using quantitative proteomics, we profiled the proteome and ubiquitome of neural stem cells and identified 116 proteins that exhibited increased protein levels and reduced ubiquitination following loss of UBE3B. These proteins were highly enriched for ones involved in synaptic processes, and we confirmed interaction of UBE3B with several key synaptic proteins, including ATP1A1, DOCK7, NLGN2, and STX12. Collectively, our findings identify a role for UBE3B in regulating social, cognitive, and motor functions, and neuronal morphogenesis and activity by fine‐tuning the synaptic proteome.\n"]