The G-protein coupled estrogen receptor (GPER) has emerged as a therapeutic target for cancer. However, the anticancer potential of GPER agonist, has been questioned due to conflicting reports suggesting its anticancer effect may stem from cytoskeleton destruction independent of GPER. In the present study, we investigated the anticancer activity and underlying mechanisms of action of both GPER agonist (G1) and antagonist (G15). Both G1 and G15 elicited concentration-dependent necroptosis in HT-29 human colon cancer and PC-3 human prostate cancer cell lines. In addition, both G1 and G15 increased ER stress marker proteins, BiP and CHOP, along with mitochondrial ROS generation. The G1- and G15-induced necroptosis were significantly inhibited by necrostatin-1 (a RIP1 inhibitor), tauroursodeoxycholic acid (an ER stress reliever), and antioxidant Vitamin E. Intriguingly, G1 and G15 significantly downregulated the expression of Gas6, an autocrine survival factor, and its receptor AXL activity. However, the induction of necroptosis and ER stress by G1 and G15, along with the attenuation of Gas6 and AXL signaling, remained unaffected by GPER knock-down, yet exhibited significant reversal upon treatment with necrostatin-1. Taken together, our results unveil a distinct mechanism of action for G1 and G15 in cancer cells, highlighting their GPER-independent induction of necroptosis.