Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a trinucleotide CAG repeat expansion in the HTT gene, with early pathological changes observed in striatal medium spiny neurons (MSNs). To investigate early, cell-type-specific transcriptional alterations and the therapeutic potential of HTT-lowering strategies, we performed single-nucleus RNA sequencing (snRNA-seq) on the striata of HttQ111/+ mice and wild-type littermate controls. Mice were treated with saline, control antisense oligonucleotide (ASO), or an HTT-targeting ASO designed to reduce HTT protein levels via RNase H-mediated degradation. Pseudobulk differential expression analysis revealed substantial transcriptional dysregulation in the Genotype contrast (674 DEGs), with strong enrichment of canonical HD gene sets in GSEA. In contrast, HTT-lowering ASO treatment resulted in only 12 significant DEGs and no enrichment of HD-related pathways, indicating limited molecular rescue. The ASO_Toxicity contrast identified 15 DEGs and showed modest enrichment of neurodevelopmental gene sets, suggesting minor, non-toxic transcriptional shifts. These findings highlight robust HD signatures in the HttQ111/+ model and suggest that optimized HTT-lowering strategies may be needed to achieve consistent transcriptomic reversal.