The generation of singlet oxygen (SO) in the presence of specific photosensitizers (PS) or semiconductor nanoparticles (NPs) and its application in photodynamic therapy (PDT) has great interest for the development of new cancer therapies. Our work focused on the identification of factors leading to the enhancement of B-Chronic Lymphocytic Leukemia (B-CLL) intracellular SO production and cell killing using Manganese (Mn) doped and undoped Zinc Oxide (ZnO) NPs as potential photosensitizers with and without PDT. Mn can enhance ZnO NPs generation of SO by targeted cells. Multi drug resistant B-Chronic Lymphocytic Leukemia (B-CLL) cells spontaneously produce high amounts of Reactive Oxygen Species (ROS) having an altered redox state in relation to that of normal B lymphocytes. These little variations of its SO intracellular concentrations could allow ZnO NPs to execute specific deadly programs against these leukemic cells with no significant damage to normal lymphocytes. A 0.5% Mn Doped ZnO NP was finally selected for further probes as it had the best killing activity in fludarabine resistant B-CLL cells, especially when combined with PDT. This could be an innovative specific therapy against resistant B-CLL probably contributing in the near future for the definitive benefit of these bad prognostic patients.