Objective: Lu-177 has a great potential for use as theranostics radiopharmaceuticals for management of cancer, evidenced by its increasing use over the past decade in nuclear medicine. The detail mechanisms of cell toxicity induced by the beta-radiation emitted from Lu-177 are not well understood. Hence, to explore the lurking mechanism of cell death, different parameters were assessed after treatment of human histiocytic lymphoma cells (U937) with Lu-177. Materials and Methods: U937 cells (1 × 106) were exposed to 3.7 and 37 MBq of Lu-177 and incubated for 24 and 48 h in humidified CO2incubator. The cell viability and apoptosis were estimated in treated and control cells by trypan blue dye exclusion and electrophoretic DNA ladder assay, respectively. Reverse transcriptase polymerase chain reaction was carried out to study the expression of anti-apoptotic genes. Results: It was found that the cell death and apoptosis were high in the cells which were exposed for a longer duration of time with 37MBq of Lu-177. These results were further confirmed by observation of downregulation of anti-apoptotic genes such as BCL-2 and BCLXL. Conclusion: It is concluded from the study that the Lu-177 induced apoptotic cell death in human histiocytic lymphoma cells by downregulation of anti-apoptotic genes.