Natural killer (NK) cell is an essential cytotoxic lymphocyte in our innate immunity. Activation of NK cells is of paramount importance in defending against pathogens, suppressing autoantibody production and regulating other immune cells. Common gamma chain (γc) cytokines, including IL-2, IL-15, and IL-21, are defined as essential regulators for NK cell homeostasis and development. However, it is inconclusive whether γc cytokine-driven NK cell activation plays a protective or pathogenic role in the development of autoimmunity. In this study, we investigate and correlate the differential effects of γc cytokines in NK cell expansion and activation. IL-2 and IL-15 are mainly responsible for NK cell activation, while IL-21 preferentially stimulates NK cell proliferation. Blockade of Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway by either JAK inhibitors or antibodies targeting γc receptor subunits reverses the γc cytokine-induced NK cell activation, leading to suppression of its autoimmunity-like phenotype in vitro. These results underline the mechanisms of how γc cytokines trigger autoimmune phenotype in NK cells as a potential target to autoimmune diseases.