Osteosarcoma (OS), the most common primary malignant bone tumor in children and adolescents, presents a significant challenge due to its high propensity for metastasis. This reality underscores the urgent need for innovative therapies targeting metastatic progression to improve patient outcomes. The present study aimed to investigate the potential of galbanic acid (GBA), a natural sesquiterpene coumarin, on the metastasis of OS cells for the first time. Utilizing bioinformatics tools, shared therapeutic targets between GBA and OS were identified, with key hub genes prioritized through network analysis. Molecular docking and dynamics simulations were performed to assess the binding affinity and stability of GBA with MMP-2, MMP-9, ADAM17, and ADAMTS5. For experimental validation, GBA was isolated from Ferula szowitsiana via thin-layer chromatography, and its effects on MG-63 cells were evaluated through a series of assays: alamarBlue assay and flow cytometry for viability and apoptosis, scratch assay for migration, transwell assay for invasive potential, fibronectin adhesion assay for cell-matrix interaction, and gelatin zymography for MMP activity. Computational analyses revealed MMPs and ADAMs as common targets of GBA and OS. Molecular docking and dynamics simulations indicated strong and stable interactions between GBA with MMP-2, MMP-9, ADAM17, and ADAMTS5. Experimental studies revealed that treatment with 100 μM GBA did not induce significant toxicity in MG-63 cells. However, GBA significantly (p < 0.01) altered cell migration, invasion, and adhesion, which was associated with a marked reduction in the enzymatic activity of MMP-2 and MMP-9. This research highlights the therapeutic potential of GBA in mitigating the metastatic properties of OS cells, suggesting a promising avenue for future treatment strategies.