By targeting one of the most important glycolytic rate-limiting enzymes, PFKFB3, using its selective inhibitor PFK15, we proved that the blockage of glycolysis in HNSCC cells not only halted tumor growth by inhibiting cell proliferation but also alleviated cancer metastasis by suppressing the formation of protrusions. Here, PFKFB3 is linked to head and neck squamous cell carcinoma.