Abstract Objectives This study aimed to investigate the role of eldecalcitol in the progression of oral squamous cell carcinoma and to explore the related mechanism. Materials and Methods The effects of eldecalcitol on the proliferation, cell cycle, apoptosis, and migration of oral cancer cells (SCC‐15 and CAL‐27) were evaluated with cell counting kit‐8, flow cytometry, quantitative real‐time polymerase chain reaction, western blotting, and scratch assay. Mouse xenograft tumor model was established to further confirm the role of eldecalcitol in the progression of oral cancer. Immunohistochemistry, quantitative real‐time polymerase chain reaction, and western blotting were used to detect glutathione peroxidase‐1 expression in oral cancer tissue and cells treated with eldecalcitol. Results Eldecalcitol was found to inhibit the proliferation and migration of SCC‐15 and CAL‐27 cells significantly, block the cell cycle in the G0/G1 phase, and enhance the apoptosis. In addition, glutathione peroxidase‐1 was downregulated by eldecalcitol and acted as an important medium of eldecalcitol in inhibiting the proliferation and migration of SCC‐15 and CAL‐27 cells, as well as promoting their apoptosis. Conclusions Eldecalcitol may inhibit the progression of oral cancer by suppressing the expression of glutathione peroxidase‐1, which may provide new insight into the application of eldecalcitol as a potential anti‐cancer drug.