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Timosaponin AIII (TAIII), a steroidal saponin isolated from the root of Anemarrhena asphodeloides Bunge, exhibits various pharmacological activities, including anti-cancer properties. TAIII inhibits the migration and invasion of various cancer cell types. However, the mechanism underlying how TAIII regulates the motility of cancer cells remains incompletely understood. In this study, we demonstrate that TAIII disrupted cell-extracellular matrix (ECM) interactions by inhibiting internalization of cell surface proteins, such as integrins. We found that TAIII inhibited cell adhesion on various ECMs. Structure-activity relationship analysis demonstrated that TAIII exhibited unique activity among the saponins from Anemarrhena asphodeloides Bunge and that the number and position of saccharide moieties were important for TAIII to exert its activity. Time lapse imaging revealed that TAIII also suppressed cell spreading on the ECM, membrane ruffling, and lamellipodia formation. Furthermore, we examined integrin β1 behaviors in response to TAIII treatment and found that TAIII blocked its internalization. These findings contribute to delineating the potential molecular mechanisms by which TAIII exerts anti-metastatic activity.