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Aortic dissection is a life-threatening cardiovascular emergency with limited pharmacological options. This study focuses on elucidating the multi-target and multi-pathway mechanisms through which morusin mitigates aortic dissection progression, integrating network pharmacology, single-cell transcriptomics and experimental validation. Multi-database analysis identified 281 morusin targets and 1741 ad-related genes, with 84 overlaps. Enrichment analyses highlighted IL-17, HIF-1 and MAPK signalling pathways as potential regulatory hubs. Protein-protein interaction network analysis identified seven key targets, all showing high binding affinity to morusin in molecular docking. Single-cell transcriptomics revealed cell-type-specific dysregulation, notably MAPK8 upregulation in fibroblasts and immune cells. In vitro, morusin dose-dependently inhibited AngII-induced vascular smooth muscle cell proliferation and modulated IL-17 pathway gene expression. In vivo, morusin attenuated aortic dilation and reduced morbidity and mortality in a BAPN-induced AD mouse model. These findings suggest that morusin mitigates AD progression by targeting key inflammatory and apoptotic pathways, supporting its potential as a multi-target therapeutic candidate.