Unlike mammals, adult zebrafish are capable of virtually full restoration of damaged brain tissues after injury. This repair is characterized by the lack of glial scar formation and the ability of adult-born neurons to establish long-distance projections to the contralateral hemisphere. The remarkable regenerative capacity of zebrafish allows for exploration of the cell types and molecular pathways necessary for effective regeneration. Brain injury induces a widespread neuroinflammatory response that recruits activated microglia to damaged regions. This is followed by proliferation of telencephalic ventricular zone (VZ) radial glia, whose neural progenitor cell progeny migrate to areas of injury and give rise to new neurons – a process that is complete in roughly 21 days post lesion (dpl). We generated a right telencephalic stab lesion in adult zebrafish using a 30-gauge Hamilton syringe. To determine the role of microglia in the injury response, we ablated these cells by injecting liposomal clodronate at the time of stab lesioning. The loss of microglia after injury was associated with a pronounced decrease in regenerative potential, as clodronate-treated animals displayed persistent tissue damage even at 90 dpl when compared to controls, suggesting that microglial signaling plays a key role in the regenerative process. Using EdU pulse labeling of proliferating cells, we found that peri-injury clodronate-induced microglial ablation significantly reduced proliferation in the parenchyma, but not the VZ. In separate experiments, we performed RNAseq to examine a brain injury model, quinolinic acid (QA)-induced excitotoxic lesioning, with even more robust regeneration than stab wound alone. Comparing injured, with and without QA, and uninjured brains allowed us to identify stab lesion-induced altered expression of many genes, a subset of which were further upregulated in response to QA injury. We have chosen candidates known to be secreted by microglia for further analysis. These findings highlight a microglial-dependent repair mechanism in the zebrafish brain that may provide strategies for promoting mammalian brain repair.