Microglial calcium signaling is rare in a baseline state but shows strong engagement during early epilepsy development. The mechanism and purpose behind microglial calcium signaling is not known. By developing an in vivo UDP fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP signals to the microglial P2Y6 receptor for broad increases in calcium signaling during epileptogenesis. UDP-P2Y6 signaling is necessary for lysosome upregulation across limbic brain regions and enhances production of pro-inflammatory cytokines-TNFα and IL-1β. Failures in lysosome upregulation, observed in P2Y6 KO mice, can also be phenocopied by attenuating microglial calcium signaling in Calcium Extruder ("CalEx") mice. In the hippocampus, only microglia with P2Y6 expression can perform full neuronal engulfment, which substantially reduces CA3 neuron survival and impairs cognition. Our results demonstrate that calcium activity, driven by UDP-P2Y6 signaling, is a signature of phagocytic and pro-inflammatory function in microglia during epileptogenesis.