Gastric Cancer (GC) presents a significant global health concern due to its high incidence and mortality rates. Despite advancements in medical treatments, drug resistance poses a major challenge in managing GC. Ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, has emerged as a key contributor to treatment resistance in GC. The pivotal role of GPX4, a regulator of ferroptosis, has garnered considerable attention in cancer research. GPX4 synthesis and expression are subject to regulation at multiple levels, including transcription, translation, and posttranslational modifications. Ongoing development of pharmacological therapeutics targeting GPX4 aims to induce ferroptosis in cancer cells. This review provides an overview of the GPX4 pathway’s involvement in GC, shedding light on the implications of ferroptosis induction in combatting cancer resilience. These findings emphasize the therapeutic potential of GPX4 in managing gastric cancer and other malignancies, presenting novel opportunities to address the challenges of treatment resistance.