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Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and fate of disease-associated microglia (DAM) remain largely unknown. We established a lineage tracing system, leveraging the expression dynamics of secreted phosphoprotein 1（ Spp1 ） to label and track DAM-like microglia during brain injury and recovery. Fate mapping of Spp1 + microglia during stroke in juvenile mice revealed an irreversible state of DAM-like microglia that were ultimately eliminated from the injured brain. By contrast, DAM-like microglia in the neonatal stroke models exhibited high plasticity, regaining a homeostatic signature and integrating into the microglial network after recovery. Furthermore, neonatal injury had a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, our findings highlight the plasticity and innate immune memory of neonatal microglia, shedding light on the fate of DAM-like microglia in various neuropathological conditions. [Display omitted] • Spp1 + microglia exhibit context- and age-dependent heterogeneity in neuropathologies • Fate mapping of Spp1 + microglia reveals irreversible removal of DAM in juvenile stroke • Neonatal DAM exhibits remarkable plasticity and regain homeostasis as stroke resolves • Neonatal DAM retains immune memory and increased sensitivity to future immune insults The fate of disease-associated microglia (DAM) in neuropathologies remains elusive. Lan et al. generated an Spp1 fate-mapping model to track DAM-like microglia and find that the plasticity of DAM is age dependent. Juvenile stroke leads to the elimination of DAM, whereas neonatal DAM exhibits high plasticity and reversibility after injury, along with heightened sensitivity to subsequent immune challenges. [ABSTRACT FROM AUTHOR]