The transition from acute-to-chronic pain is important because underlying mechanisms may reveal targets for the treatment of chronic pain. Spinal cord microglial activation results from persistent neuronal hyperexcitability, and this can trigger feedforward synaptic plasticity that contributes to chronic pain. We used a targeted, inducible genetic microglial depletion strategy in the clinically relevant tibial fracture/casting model of complex regional pain syndrome (CRPS) to interrogate the contribution of microglia to pain progression. When microglia were transiently depleted at the acute-to-chronic phase transition, we observed complete resolution of established mechanical sensitivity which coincided with the timeframe of full repopulation of microglia. These repopulated microglia were morphologically distinct from control microglia, suggesting they may exhibit a unique transcriptome. We studied this transcriptome by RNA-sequencing FACS-isolated microglia and utilizing a combination of Deseq2 and weighted gene co-expression network analysis (WGCNA) to identify networks of genes contributing to the pain resolution. Overall, transcriptome analysis characterized repopulated microglia as highly active, phagocytic cells, that survey and respond to their environment in the context of injury. Microglial targets identified in the mouse pain resolution context were further validated in human dorsal-horn, lumbar spinal cord microglia nuclei. Overlap with the human dataset revealed targets with high translational potential. R35 GM127906. Foundation for Anesthesia Education and Research (FAER) Mentored Research Training Grant. Rita Allen Foundation Award in Pain. Department of Anesthesiology, Perioperative & Pain Medicine at Stanford University.