Oral squamous cell carcinoma (OSCC) is the most common malignancy among head and neck squamous cell carcinomas. Targeted therapy plays a crucial role in the treatment of OSCC. However, new and more targets are still needed to develop. Stanniocalcin-1 (STC-1) is a glycoprotein hormone that affects the progression of cancers. However, the potential role of STC-1 in OSCC progression remains to be explored. Here, we aimed to elucidate the role of STC-1 in OSCC. We revealed that STC-1 was highly expressed in OSCC tissues and is correlated with poor patient prognosis. Knockdown of STC-1 significantly suppressed the growth of OSCC cells and restrained glycolysis by reducing glucose consumption, ATP production, and lactate levels. Mechanistically, STC-1 ablation inhibited the PI3K/Akt pathway, reducing the phosphorylation levels of PI3K and Akt. In conclusion, STC-1 depletion restrained OSCC cell growth and glycolysis via PI3K/Akt pathway and has the potential to serve as a therapeutic target for OSCC.