BACKGROUND: Atherosclerosis (AS) is a major cause of cardiovascular diseases, with OX-LDL-induced VSMC dysfunction being a critical pathogenic driver of AS development. Saikosaponin D (SSD), a bioactive compound, shows therapeutic potential, but its mechanism in AS is unclear. METHODS: An atherosclerotic cell model was established by treating hVSMCs with OX-LDL. Intracellular ROS was detected via a fluorescent probe, MDA content and SOD activity via biochemical kits. Inflammatory cytokines (IL-6, IL-8 and TNF-α) were quantified by ELISA. Lipid parameters (TG, LDL and HDL) were analysed biochemically, and intracellular lipid accumulation was assessed via Oil Red O staining. Autophagy (LC3B and p62) and senescence-related (p16 and p21) protein expression was detected by WB, with cellular senescence further assessed via SA-β-gal staining. SSD's potential targets were predicted via bioinformatics (CTD, SwissTargetPrediction and GeneCards). SSD-EPHB2 interaction was predicted by AutoDock Vina docking (visualised by PyMOL), and its stability was evaluated by using iMODS-based NMA. EPHB2's functional role was confirmed via its overexpression in hVSMCs. RESULTS: SSD significantly attenuated OX-LDL-induced oxidative stress, inflammation, lipid accumulation, autophagic flux impairment and cellular senescence in hVSMCs. Bioinformatics analysis pinpointed EPHB2 as a hub gene. Molecular studies confirmed that SSD directly binds to EPHB2 and downregulates its expression. Crucially, overexpressing EPHB2 abolished all the protective effects of SSD. CONCLUSION: SSD alleviates OX-LDL-induced hVSMC dysfunction by inhibiting EPHB2, highlighting the SSD-EPHB2 pathway as a potential therapeutic target for AS.