The incidence of various types of cancers is increasing every year. Among these, leukemia is extremely common, and thus, developing novel drugs to combat leukemia is crucial. In this study, we designed and synthesized several hybrids and obtained a new lead molecule 5a, with a strong therapeutic effect on leukemia. The results indicated that most hybrids effectively inhibited the growth of leukemia cells, HCT-116, and A549 cancer cells with an IC<sub>50</sub> of <10 μM. Among these hybrids, 5a and 4h showed significant anticancer activity against CCRF-CEM, with IC<sub>50</sub> values of 0.895 μM and 0.555 μM, respectively. Particularly, 5a had lower toxicity to L02 than chlorambucil (CLB) and doxorubicin (Dox), and the high selectivity was also reflected in the normal human B lymphoblast cell line (IM9). Upon investigating the mechanism of action, we found that 5a downregulated Bcl-2 and caused DNA double-stranded breaks (DSBs) to induce several genotoxic stress responses. The results of the flow cytometry assay showed that 5a was a non-specific molecule in the cell cycle. Furthermore, 5a did not affect total ROS levels but significantly improved the activity of glutathione peroxidase (GPx). Preliminary studies showed that nitrogen mustard exerted an efficient effect, and 5a can combine the advantages of artemisinin and nitrogen mustard and exhibit effects superior to either. This study showed that 5a should be further investigated as a therapeutic compound against leukemia.