Oral squamous cell carcinoma (OSCC) is one of the most commonly diagnosed cancers worldwide. Chromosome 20q is a hotspot for gene amplification in OSCC and the serine/threonine kinase STK15 (also named Aurora-A) maps to 20q13. The amplification and over-expression of STK15 is common in neoplasia but the functional and clinical impact of STK15 in OSCC remains poorly understood. STK15 copy number is amplified in 12% of OSCCs and nuclear STK15 protein expression increases with tumour progression. In vivo elevated nuclear STK15 protein expression is significantly associated with the worse prognosis of OSCC patients. The combination of high nuclear STK15 and Ki-67 expression has a 2.55-fold hazard for cancer-associated mortality. In vitro knockdown of STK15 reduced the oncogenic phenotypes of OECM-1 cells. Injection of lentivirus carrying shRNA vectors against STK15 significantly reduced the growth of SAS xenografts on nude mice. Knockdown of STK15 also induced autophagy and apoptosis of OSCC cells. Our data provide evidence that STK15 is oncogenic for OSCC and that its nuclear expression is a predictor of clinical behaviour. Knockdown of STK15 could be a potential therapeutic option in OSCC and other tumours.