Huntington’s disease (HD) is a currently incurable neurodegenerative disorder that manifests itself through motor and cognitive symptoms due to a predominant loss of striatal projection neurons (SPNs) in the striatum. Although HD is a neurodegenerative disease, growing evidence show that developmental alterations could be a key factor in the disease, determining the future vulnerability of certain cell types, such as SPNs. Here we show an early HD-related gene expression pattern elucidated by bulk and single-cell RNA sequencing performed on wt and HD isolated mouse striatal primordia at different developmental stages combined with histological analysis. Our results reveal early alterations in cell cycle progression, neurogenesis and cell fate determination in HD embryos, specifically affecting the indirect SPNs (iSPNs) lineage formation. Moreover, iSPNs undergo apoptosis and those that persist and constitute the indirect pathway show axonal projections alterations at postnatal stages in HD. Using scRNA-seq from mouse and human samples, we were able to identify the striatal neural progenitor cells (NPCs) responsible for the cell fate balance alterations in the in striatal populations during early development. In conclusion, here we show that an abnormal developmental trajectory in a subset of striatal NPCs can be the cause of developmental alterations observed in HD. Identifying these pathways is crucial to develop new strategies to restore neuronal homeostasis, protect striatal iSPNs and prevent HD progression.