Burkitt lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) and it appears to be one of the most common childhood cancers in equatorial areas. Unprecedented gains have been made in the cure rates for BL during the past two decades and these reflect steady improvements in treatment protocols and a multidisciplinary approach to patient care. However, the life-threatening side effects associated with conventional treatment urge us to explore new strategies. Arsenic trioxide (ATO), a natural product that has improved the prognosis of acute promyelocytic leukemia (APL) from highly fatal to highly curable, has also been proven to be effective in treating BL cell lines through multiple pathways in our study. Our data indicates that ATO can inhibit the proliferation of BL cell lines through 1) arresting the cell cycle; 2) decreasing the respiratory function and transmembrane potential of mitochondrial; and 3) downregulating the expressions of Survivin, Bcl-2, MCL-1, and VECF. We therefore suggest that dissecting the pharmaceutical mechanism of ATO at the molecular and cellular levels may be a good strategy to explore the value of traditional natural products in treating high malignant Burkitt lymphoma.