Poly(ADP-ribose) (PAR) glycohydrolase (PARG) serves as a key enzyme in the hydrolysis of PAR. Deficiency in PARG increases cell death upon exposure to γ-irradiation or treatment with an alkylating agent. This makes PARG a prospective therapeutic target for cancer. Our previous research illustrated that MO2455, leading to PAR accumulation, exerts cytotoxicity on B cell lymphoma cells by disrupting the B cell pathway. In this study, we explored and compared the cellular mechanisms underlying MO2455-induced cell death in histiocytic lymphoma U937, monocytic leukemia THP-1, and T lymphoblastic leukemia CCRF-CEM cells. MO2455 triggered cell death in all cell types at similar concentration ranges. Cell death was observed through the appearances of the apoptotic subG1 fraction and annexin-V+/propidium iodide (PI)- fraction, followed by the annexin-V+/PI+ fraction in U937 cells after MO2455 treatment. U937 cells showed a decreased mitochondrial membrane potential and an early increase in ɣ-H2AX levels 5 hrs after MO2455 treatment, suggesting a rapid DNA damage and apoptosis induction process. THP-1 also showed an increase in the apoptotic subG1 fraction and then the appearance of the annexin-V+/PI+ fraction. CCRF-CEM showed a rapid induction of the annexin-V+/PI+ fraction. Taken together, MO2455 can effectively induce cell death through some common and distinct processes in various types of lymphoma and leukemia cells.