Cancer is among the most serious diseases endangering human life and health. At present, traditional Chinese medicine has showed excellent prospects for wide application in tumor treatment. In this study, fourteen novel bisbenzylisoquinoline derivatives were designed and synthesized by Suzuki-Miyaura reaction of 5-bromotetrandrine with a variety of arylboronic acids. The anti-tumor activities of these new compounds on human lung cancer cells (A549) and murine leukemia cells (P388) were evaluated by using the CCK-8 method. Apoptosis and cell cycle were detected by flow cytometry. These compounds exhibited better activities than tetrandrine itself on A549 cells. Among them, compound 1 exhibited the most significant cytotoxic effects. Preliminary mechanistic studies indicated that the ant proliferative efficacy of compound 1 was mediated by its induction of apoptosis and cell cycle arrest at the S and G2 phases. Fourteen new tetrandrine derivatives were synthesized and tested for their anti-tumor activities in vitro. All compounds showed stronger cytotoxic effects than the parent compound tetrandrine in A549 cell lines. These findings will contribute to the future design of more effective anti-tumor agents in lung cancer therapy.