Background: Single-cell sequencing technologies are transforming our ability to resolve the cell type-specific factors contributing to brain diseases. Mouse models are critical tools to study the pathophysiology of epilepsy. The intra-amygdala kainic acid model in mice has emerged as one of the leading models of drug-resistant temporal lobe epilepsy, displaying unilateral neuropathology and broad resistance to anti-seizure medicines. Additional insights into the cell and molecular changes in this model may help us understand the mechanisms underlying drug resistance and how different cell types adapt to chronic seizures in this model. Here, we generated a single-nuclei RNA sequencing dataset using the 10X platform from hippocampal tissue from the intra-amygdala kainic acid mouse model. A total of 30428 nuclei from eight mice were sequenced, comprising samples from four epileptic and four control mice. After quality control, cell types were annotated, and we identified all major transcriptomic subtypes of hippocampal cells in our data. Differential gene expression analysis revealed cell-subtype specific dysregulation in the epileptic mice which extended across the major subdomains of the hippocampus. Cell-cell communication analysis revealed increased connectivity from interneurons to multiple other cell subtypes, suggesting potential mechanisms of adjustment to chronic neuronal hyperexcitability. Microglia and astrocytes displayed altered expression of genes associated with anti-inflammatory responses, indicating potential protective adaptations.