Experience-dependent maturation of neocortical circuits is required for normal sensory and cognitive abilities, which are distorted in neurodevelopmental disorders. We have tested whether experience-dependent neocortical modifications require Ube3a, an E3 ubiquitin ligase whose dysregulation has been implicated in autism and Angelman syndrome (AS). Using visual cortex as a model, we demonstrate that experience-dependent maturation of excitatory cortical circuits is severely impaired in AS mice deficient in Ube3a. This developmental defect is associated with profound impairments in neocortical plasticity. Remarkably, normal plasticity is preserved under conditions of sensory deprivation, but rapidly lost by sensory experiences. The loss of neocortical plasticity is reversible, as late-onset visual deprivation restores normal synaptic plasticity. Further, Ube3a-deficient mice lack ocular dominance plasticity in vivo when challenged with monocular deprivation. These results show that Ube3a is necessary to maintain plasticity during experience-dependent neocortical development, and suggest that loss of neocortical plasticity contributes to deficits associated with AS.