Background: Tuberous sclerosis complex (TSC) frequently causes epilepsy, but cell-type-specific molecular alterations in human lesions remain incompletely understood. Methods: We performed single-nucleus RNA sequencing of cortical tissue from three TSC and three surgical control donors, with single-nucleus chromatin accessibility profiling in two donors per group from the same cohort. Donor-level pseudobulk differential analyses were combined with functional enrichment, inferred cell communication, and motif analyses. Results: Among the six cell types displayed in the main comparison, microglia had the most differentially expressed genes (872; 282 upregulated and 590 downregulated). Downregulated genes were enriched for lysosomal and lipid-storage processes. Inferred APP-CD74 input to microglia was higher for most source cell types, whereas APP-SORL1 changes varied by source. Chromatin analysis identified 9283 differentially accessible regions. Predicted regions linked to ABCA1, ATP6V0A1, and GPNMB showed decreased accessibility, concordant with lower RNA expression. Donor-averaged TFEB- and TFE3-associated chromatin variation across regions (chromVAR) scores were lower in TSC. Conclusions: These exploratory findings suggest microglial remodeling involving lysosomal and lipid-storage processes. It may provide a molecular basis for further investigation of microglia in epileptogenesis.