Aims: Adenoid cystic carcinoma (ACC) progresses from indolent biphasic (epithelial–myoepithelial) cribriform patterns to aggressive epithelial-dominant solid patterns, including high-grade transformation (HGT). We aimed to identify determinants of clinical aggressiveness and define therapeutic targets by elucidating mechanisms of architectural remodeling and HGT. Methodology: We conducted a retrospective clinicopathological analysis of 47 ACC patients with long-term follow-up. Spatial transcriptomics mapped gene expression and inferred copy-number alterations (CNAs) across histologic transitions in four selected cases. Inferred CNA results were validated using bulk whole-exome sequencing. Results: Loss of biphasic architecture—the complete replacement of myoepithelial cells by epithelial cells—was a robust independent predictor of poor survival. Spatial and single-cell analyses revealed that, during progression to the solid pattern, MYB expression shifts from myoepithelial to epithelial cells and increases in overall expression levels. In biphasic tumors, the shift from myoepithelial-dominant to balanced architecture was associated with increased epithelial-mediated cell–cell interactions, with enrichment of NOTCH receptor–ligand pairs among top myoepithelial-to-epithelial interactions. In contrast, tumors with complete loss of biphasic architecture, including HGT, showed markedly reduced NOTCH expression. HGT was characterized by whole-genome doubling, and spatially resolved CNA analysis demonstrated stepwise genomic evolution culminating in this event. Conclusion: Loss of biphasic architecture is a key prognostic determinant in ACC. Spatial redistribution of MYB and NOTCH signaling and stepwise genomic instability drive malignant progression. Whole-genome doubling is strongly associated with HGT and poor prognosis. MYB represents a durable oncogenic dependency and a promising universal therapeutic target, even in the most aggressive HGT subtypes.