The innate immune system is required for host defense against pathogens, but emerging evidence indicates that it also contributes to normal tissue development and remodeling. Central nervous system (CNS) glial cells including astrocytes and microglia regulate synapse development and are the primary source of immune signals in the CNS. Here we show that the IL-1 family cytokine Interleukin-33 (IL-33) is expressed by developing astrocytes and activates microglia to regulate neuronal synapse pruning. We localized IL-33 expression to developing astrocytes and identified a unique transcriptomic profile associated with IL-33 expression in astrocytes. The obligate IL-33 receptor IL1RL1(ST2) was only detected in microglia. Transcriptomic analysis of microglia from Il33-/- mice revealed suppressed NF-κB -dependent immune activation and defects in neuronal synapse engulfment, whereas exogenous IL-33 promoted synapse engulfment and led to synapse depletion. Conditional deletion of IL-33 from astrocytes resulted in increased numbers of spinal cord sensorimotor synapses, and Il33-deficient animals had deficits in sensorimotor startle behaviors. Thus, astrocyte-encoded IL-33 tunes microglial activation state to regulate synapse pruning during neural circuit maturation, revealing a novel inflammatory pathway required for normal synapse remodeling and CNS development.