This study highlights the significance of supercharged NK (sNK) cells in inducing the lysis and differentiation of tumors at much higher levels compared to primary activated NK cells. sNK cells-induced higher release of growth factors, cytokines, and chemokines when compared to primary activated NK cells. When we used a similar level of IFN-γ from primary activated NK cells and sNK cells, the IFN-γ secreted from sNK cells exhibited greater potential to induce differentiation in both oral and pancreatic tumors. It is long known in the field of NK cells that primary NK cells induce significant lysis of stem-like/poorly differentiated tumors, but differentiated tumors are generally resistant to primary NK cell-mediated lysis. sNK cells, unlike primary activated NK cells, are found to highly target stem-like as well as differentiated tumors, indicating sNK cells can target not only tumors specific to NK cells but also those targeted by CD8+ T cells. Differentiation by sNK cells was inhibited less by the antibodies to IFN-γ and TNF-α when compared to that mediated by the primary activated NK cells, suggesting the role of other unexplored mechanisms in sNK cell-induced tumor differentiation. Overall, this study suggests the role of sNK cells in targeting the heterogeneous population of tumors, likely mediating the functions of both NK cells and T cells in controlling tumors, and inducing them to be effectively targeted by chemotherapy.