Lung cancer still remains a leading cause of cancer mortality in the world. Obatoclax mesylate (OM), a B cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2) family antagonist, is a potential antitumor drug. However, its poor aqueous solubility restricts its clinical application. Although these inherent defects, nanotechnology can be used to improve the solubility and tumor target of OM, promoting its antitumor efficiency. In the present study, the poly(lactic-coglycolic acid) (PLGA) was used and combined with red blood-cell membrane (RBCm) to explore if OM-loaded RBCm nanoparticles could improve the antitumor efficacy of OM for the treatment of lung cancer with relatively lower side effects compared with the free OM. The good physicochemical stability of the prepared RBCm-OM/PLGA nanoparticles was confirmed, and the optimal size of 153 nm was screened out, along with sustained drug release behavior. We found that RBCm-OM/PLGA nanoparticles effectively reduced the proliferation of lung cancer cells. Additionally, RBCm-OM/PLGA nanoparticles considerably induced apoptosis in lung cancer cells by reducing Bcl-2 expression levels, accompanied with the improved Cyto-c releases in cytoplasm and Caspase-3 activation. Mitochondrial membrane potential was also obviously impaired in lung cancer cells incubated with RBCm-OM/PLGA nanoparticles. Compared with free OM, RBCm-OM/PLGA nanoparticles could greatly prolong the drug circulation time in vivo and upgraded the drug concentration accumulated in tumor tissue. Furthermore, RBCm-OM/PLGA nanoparticles exerted stronger antitumor efficacy in vivo against lung cancer progression with superior safety. Therefore, RBCm-OM/PLGA nanoparticles provided new potential for lung cancer therapy with the improved safety and therapeutic effect.