Medicinal plants are affluent sources of several effectual natural drugs. Among them cordycepin which is extracted from Cordyceps militaris is a hopeful chemotherapy agent due to its extensive anti-inflammatory, anti-proliferative, antioxidant, and antitumor characteristics. This study investigated the efficacy of cordycepin in the context of human gastric cancer SGC‑7901 and searched for the cell death procedure. Cordycepin incorporates mitochondrial-mediated apoptosis in SGC‑7901 cells with the help of regulating mitochondrial extrinsic pathways by inhibition of A3AR and drive activation of DR3, which promote the activation of PI3K/Akt protein expression as well as collapse of mitochondrial membrane potential (MMP). In addition, phosphorylation of PI3K/Akt and DNA damage by cordycepin induced the production of reactive oxygen species (ROS), and mediates SGC‑7901 cell cycle cessation at S phase. Collectively, this study suggests that cordycepin might be effective as a modern chemotherapy drug for gastric cancer.