S100A4 is a calcium-binding protein that regulates cytoskeletal dynamics, motility, and epithelial–mesenchymal transition (EMT). Upon binding to calcium in its EF-hand domains, S100A4 undergoes a conformational shift that exposes its hydrophobic pockets, which are required for interacting with downstream effectors that drive migration and proliferation (9). Dysregulated S100A4 activity has been implicated across multiple malignancies, with elevated expression commonly observed in oral squamous cell carcinoma (OSCC), a metastatic form of head-and-neck cancer. Although small-molecule inhibitors targeting S100A4’s hydrophobic interaction surfaces have been explored, no therapeutic strategy has been developed to block its calcium-dependent activation, representing an unmet mechanistic target. Here, we designed and screened for three engineered small-molecule inhibitors that bind to the EF-hand of the calcium-binding pocket in S100A4. Using a protein-based drug screening platform, we evaluated each compound and its ability to bind calcium-dependent S100A4 in silico. One candidate observed effective binding to the EF-hand region and demonstrated the potential for interference with calcium binding, and was identified as a suitable molecule for further in vitro testing. These findings establish the feasibility of designing EF-hand–targeted inhibition of S100A4 in silico for studying an unexplored therapeutic strategy aimed at mitigating S100A4-driven progression in oral and head-and-neck cancers.