Significance The steroid hormone progesterone is highly involved in different physiological–pathophysiological processes, including bone formation and cancer progression. Understanding the working mechanisms, especially identifying the receptors of progesterone hormones, is of great value. In the present study, we identified GPR126 as a membrane receptor for both progesterone and 17-hydroxyprogesterone and triggered its downstream G protein signaling. We further characterized the residues of GPR126 that interact with these two ligands and found that progesterone promoted the progression of a triple-negative breast cancer model through GPR126-dependent Gi-SRC signaling. Therefore, developing antagonists targeting GPR126-Gi may provide an alternative therapeutic option for patients with triple-negative breast cancer.