Cleavage and polyadenylation specific factor 6 (CPSF6), a member of serine/arginine-rich protein family, is implicated in HIV-1-infection and replication. Overexpression of CPSF6 predicts poor prognostic outcomes of breast cancer. However, the expression and possible function of CPSF6 in lung adenocarcinoma (LUAD) still needs to be explored. Here, we found that CPSF6 is significantly higher expressed in tumor tissues than normal tissues in multiple cancer types. Besides, CPSF6 plays a significant risky role in LUAD that is associated with overall survival (HR=1.337, P=0.051) and disease-specific survival (HR=1.4739, P=0.042). CPSF6 mRNA was up -regulated in LUAD tissues by analyzing publicly available datasets from Gene Expression Omnibus (GEO). Further survival analysis on The Cancer Genome Atlas (TCGA) dataset suggested a close correlation between CPSF6 expression and overall survival, and disease-free survival of LUAD patients. Inhibition of CPSF6 expression by lentivirus-mediated RNA interference (RNAi) in two LUAD cell lines (A549 and NCH-H1299) caused a significant reduction in cell proliferation, colony formation and a notable induction in apoptotic rate. CPSF6 knockdown in xenograft tumors inhibited LUAD cell growth in vivo. Moreover, we identified differentially expressed genes with CPSF6 inhibition by Microarray analysis, and pathway analyses revealed that CPSF6 knockdown resulted in the dysregulation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. Collectively, our results are the first to demonstrate that CPSF6 functions as an oncoprotein by regulating cancer-related pathways in LUAD.