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Post-operative delirium (POD) is a serious complication of surgery particularly in older adults, characterized by acute disturbances in consciousness and cognition and associated with increased mortality and long-term cognitive impairment. Despite its clinical relevance, the underlying pathophysiology remains poorly understood. To address this, we performed multi-omics profiling of live brain tissue from patients undergoing neurosurgery. Single-nucleus RNA sequencing revealed POD-specific transcriptional alterations in glial cells, especially microglia, characterized by enhanced neuroinflammatory signatures. Astrocytes also exhibited changes in synaptic and migratory pathways. Upstream analysis implicated external cytokines as potential drivers of glial responses, while downstream analysis linked POD to encephalitis and dementia. DNA methylation profiling identified immune-related epigenetic alterations, suggesting a regulatory role in POD-associated neuroinflammation. Integration of bulk methylation and cell type-specific transcriptomic data suggested that epigenetic changes may influence gene expression during POD pathogenesis. These findings provide the convincing evidence of neuroinflammation and glial involvement as the pathophysiological mechanism of POD based on the first multi-omics analysis using patient brain tissue.