Recently, long non-coding RNAs have gained an increasing amount of attention in treating lung cancer. However, a full understanding of how CCAT1 lncRNA works against proliferation is not yet available. Therefore, we assess the impact of CCAT1 on the lung cancer cell proliferation, apoptosis, and doxorubicin (DOX) sensitivity, and the involvement of miR-181a/CPEB2 pathway. For this purpose, lung cancer A549 cells were exposed to siRNA against CCAT1 and DOX and cell viability were measured by MTT assay. ELISA was used to evaluate cell apoptosis. The protein and mRNA expression levels of apoptotic markers, miR-181a and CPEB2 were measured by western blot and qRT-PCR. Knock-downing CCAT1 inhibited the cell viability of A549 cells. In addition, si-CCAT1 treatment increased apoptosis in both cell lines via modulating the anti- and pro-apoptotic markers. Si-CCAT1 increased the levels miR-181a and decreased CPEB2 in A549 cells. In conclusion, our study has provided strong evidence that lncRNA CCAT1 decreased the sensitivity to doxorubicin in lung cancer cells by regulating the miR-181a/CPEB2 axis.