The suppressor of zeste-12 protein (SUZ12), a core component of Polycomb repressive complex 2 (PRC2), is implicated in transcriptional silencing by generating di- and tri-methylation of lysine 27 on histone H3 (H3K27Me3). Although SUZ12 is known to be of great importance in several human cancer tumorigenesis, limited data are available on the expression profile and functional role of SUZ12 in non-small cell lung cancer (NSCLC). Here, we determined the expression level of SUZ12 in 40 paired clinical NSCLC tissues and adjacent normal tissues by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The results showed that SUZ12 was anomalously expressed in NSCLC tissues compared to adjacent noncancerous tissues (P<0.05) and was highly correlated to tumor size, lymph node metastasis, and clinical stages (P<0.05). Additionally, siRNA-mediated knockdown of SUZ12 could inhibit tumor cell growth, migration, and invasion, indicating that SUZ12 might function as an oncogene in NSCLC initiation and progression. Furthermore, we found that SUZ12 silencing significantly reduced the expression levels of transcription factor transcription factor E2F1 (E2F1) as well as potential metastasis promoters Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) and roundabout homolog 1 (ROBO1) through Western blot analysis. Altogether, we provide evidences suggesting that SUZ12 is an oncogene in NSCLC and can regulate NSCLC cells proliferation and metastasis partly via reducing E2F1, ROCK1, and ROBO1. Thus, SUZ12 may represent a new potential diagnostic marker for NSCLC and may be a novel therapeutic target for NSCLC intervention.