Huntington's disease (HD) is marked by widespread cellular dysregulation. To understand disease mechanisms, we and others have utilized bulk and single-cell transcriptomics, which provide cell-type information but limited spatial information. We used 10× Genomics Visium spatial transcriptomics integrated with matched single-nuclei RNA sequencing (snRNA-seq) in the rapidly progressing HD R6/2 mouse brain (post-natal day 0 [P0], 4 weeks, and 12 weeks). Our data suggest regional, temporal, and cell-type-specific regulatory pathways that establish distinct gene expression changes. Synaptic dysfunction is observed broadly throughout the brain, whereas we observed early dysregulation of the transcription factor 4 (Tcf4) that may drive cortical changes. Mitochondrial deficits are the earliest changes, beginning at P0 in the striatum. Striatal identity genes show early increased expression that becomes progressively downregulated. Finally, we identified a time-dependent dysregulation of neuropeptide Y signaling and potential interaction with the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway, which may be involved in the imbalance between Drd1 and Drd2 neuron vulnerability.