Abstract. Low expression of the clock gene PER2 is closely related to carcinogenesis and the development of cancer; however, the mechanism of the low expression of PER2 that led to cell malignant transformation remains unclear. This study used RNA interference (RNAi) technology to silence PER2 in SCC15 human oral squamous cell carcinoma (OSCC) cells. Then it was found that the ability of cancer cell proliferation, migration, and invasion were markedly increased (P<0.05), and the ability of cancer cell apoptosis and the number of cells in G1/G0 phase were markedly reduced (P<0.05) after PER2 knockdown. PER2 knockdown increased the expression of MDM2, MMP2, and VEGF mRNA (P<0.05), and decreased the expression of p53, Bax, and TIMP-2 mRNA (P<0.05). The in vivo experiments also proved that the tumorigenicity of SCC15 cells was significantly enhanced after PER2 silence (P<0.05). Overall, these results show that PER2 through the regulation of the numerous important downstream tumor-related genes, plays a major role in tumor suppression, and it may be a novel molecular target for cancer treatment.