Objective: This study aims to elucidate the activation status and transcriptional heterogeneity of astrocytes in the mouse brain during the progression of Huntington’s disease (HD) and to screen for and identify differentially expressed molecules on the key issue. Methods: (1) Immunofluorescence was employed to examine the transformation of HD astrocytes into reactive astrocytes at both the early and late stages of the disease, and this transformation was subsequently verified by RT-qPCR; (2) Single-cell dissociation and magnetic bead sorting techniques were utilized to isolate astrocytes from mouse brains for subsequent transcriptome sequencing; (3) Bioinformatics analysis was conducted to identify differentially expressed genes (DEGs) and to perform GO functional enrichment analysis on the transcriptome data from the early and late stages of HD; (4) Genes related to the progression of HD were selected for Protein-protein interaction network (PPI-network) analysis, and the expression of core genes was validated. Results: In the late stage of HD, astrocytes transform into A1-type reactive astrocytes; in the early stage of the disease, DEGs in HD mouse astrocytes were predominantly associated with synaptic functions, such as synaptic cleft and the maintenance of synaptic structure, whereas in the late stage, they were mainly involved in chemotactic activity, signal transduction, and cellular response functions; core genes of astrocytes during HD progression were mainly related to angiogenesis, RNA splicing, metabolism, and muscle movement. Conclusion: In the early stage of HD, astrocytes influence neuronal development and synaptogenesis. Later in the disease course, they transform into neurotoxic type A1 reactive astrocytes. Astrocyte heterogeneity genes that are independent of the aging process can serve as effective molecular markers for the progression and prediction of HD, and the findings are expected to provide a new reference for the early detection and treatment of HD.