Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer and is highly malignant. Despite advances in diagnostics and treatment, the prognosis for ccRCC remains poor. The dual nature (promotion or inhibition) of S100A2 in different cancer types shows the complex involvement of its tumorigenesis, but its effect in ccRCC remains unclear. In this study, we first elucidate the tumor-promoting function of S100A2 in ccRCC by reprogramming glycolysis. Mechanistically, we demonstrate that S100A2 accelerates cancer progression through its interaction with the transcription factor HNF1A, leading to activating GLUT2 transcription. The upregulation of GLUT2 significantly enhances glucose uptake by cancer cells, thereby fueling augmented glucose metabolism and fostering the malignant progression of ccRCC. Collectively, our findings highlight the pivotal role of the S100A2-HNF1A-GLUT2 axis in promoting migration and invasion of ccRCC by amplifying glycolysis and suggest that targeting the S100A2-HNF1A-GLUT2 axis is clinically relevant for the treatment of metastatic ccRCC.