Microglia, the resident macrophages of the central nervous system, exhibit region-specific transcriptional diversity and age-related changes. A genome-wide analysis of microglia from discrete brain regions in mice revealed distinct regional transcriptional identities and age-related variations. In young adults, cerebellar and hippocampal microglia showed higher immune vigilance, while aging led to a loss of distinction in hippocampal phenotype and increased distinction in cerebellar microglia. Microglial diversity may enable region-specific homeostatic functions but also contribute to age-related neurodegeneration. The study identified key gene expression patterns and pathways involved in immune regulation and bioenergetics, showing that microglia in different brain regions have distinct functional roles. Ageing affected these patterns differently, with cerebellar microglia showing greater sensitivity to age-related changes. The data suggest that microglial diversity is superimposed on a core profile distinguishing them from systemic macrophages, and that aged microglia retain some aspects of their young adult identity but do not adopt a macrophage-like phenotype. The findings highlight the importance of regional differences in microglial function and their potential role in age-related neurological disorders.Microglia, the resident macrophages of the central nervous system, exhibit region-specific transcriptional diversity and age-related changes. A genome-wide analysis of microglia from discrete brain regions in mice revealed distinct regional transcriptional identities and age-related variations. In young adults, cerebellar and hippocampal microglia showed higher immune vigilance, while aging led to a loss of distinction in hippocampal phenotype and increased distinction in cerebellar microglia. Microglial diversity may enable region-specific homeostatic functions but also contribute to age-related neurodegeneration. The study identified key gene expression patterns and pathways involved in immune regulation and bioenergetics, showing that microglia in different brain regions have distinct functional roles. Ageing affected these patterns differently, with cerebellar microglia showing greater sensitivity to age-related changes. The data suggest that microglial diversity is superimposed on a core profile distinguishing them from systemic macrophages, and that aged microglia retain some aspects of their young adult identity but do not adopt a macrophage-like phenotype. The findings highlight the importance of regional differences in microglial function and their potential role in age-related neurological disorders.