The Hippo pathway plays a major role in development and organ size control, and its dysregulation contributes to tumorigenesis. WWTR1 is a transcription coactivator acting downstream of the Hippo pathway. Recently, WWTR1 has been reported to be overexpressed in several human cancers including lung cancer. However, the molecular mechanism of WWTR1 regulating lung cancer aggressiveness remains ambiguous. In the present study, we analyzed the expression of WWTR1 in NSCLC cell lines and found that WWTR1 was overexpressed at both the mRNA and protein levels. Knockdown of WWTR1 by siRNA interference in A549 cells significantly inhibited cell proliferation and increased paclitaxel-induced apoptosis. On the other side, WWTR1 overexpression in HBE cell line promoted cell proliferation and inhibited apoptosis. In addition, we found that the decreased proliferation after siRNA treatment was due to cell cycle arrest. Further analysis showed that WWTR1 could induce cyclin A, connective tissue growth factor (CTGF) expression, and inhibit caspase3 cleavage. In conclusion, WWTR1 promotes malignant cell growth and inhibits apoptosis by cyclin A and CTGF regulation.