Traumatic brain injury (TBI) has been characterized as a silent epidemic with growing incidence rates worldwide. Recently, single cell genomics has revealed multiple microglial subtypes activated during inflammation, and emerging evidence suggests that distinct subtypes contribute to age-related differences in neurodegeneration and neuroprotection. In this thesis, I test the hypothesis that differential microglial activation states contribute to the worsened outcomes to TBI associated with aging. Using single-nucleus RNA and ATAC sequencing, I describe cell type specific transcriptional and epigenomic changes in microglia in the context of TBI in young vs. aged mice. I found substantial transcriptional effects of TBI in microglia in both young and aged mice. Regulatory network models predict common repression of homeostatic genes but differential activation of regulatory activity with transcription factors like Nfe2l2 and Runx1 in rescuing and repressing a neuroprotective state of microglia.