Multiple sclerosis (MS) is a neuroinflammatory disease of the CNS characterized by demyelinating lesions. Lesion expansion contributes to disability progression, whereas remyelination may restore neurological function. How these divergent outcomes relate to microglial states remains incompletely understood. Using single-cell-resolution spatial transcriptomics, we compare lesions containing foamy to those containing ramified microglia in postmortem human brain tissue. We find distinct cellular and molecular signatures spatially associated with microglial morphology. Lesions with ramified microglia display gene expression profiles associated with myelin stability and axonal support, consistent with an environment permissive for repair. In contrast, lesions with foamy microglia exhibit immune activation, immunoglobulin production, complement activity, iron dysregulation, immune-oligodendrocytes, and demyelination. These findings show that molecular programs linked to lesion pathology are spatially segregated in association with microglial state, indicating distinct immune-glial niches associated with lesion expansion and repair.