Chronic atrophic gastritis (CAG) is a prevalent and progressive gastric disorder that can lead to significant gastric dysfunction and an increased risk of gastric cancer. Oxidative stress plays a central role in the pathogenesis of CAG, contributing to cellular damage and inflammation. The nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is crucial in cellular defense against oxidative stress by regulating the expression of antioxidant and cytoprotective genes. Activation of this pathway has shown promise in mitigating oxidative damage and promoting mucosal healing in CAG. This review aims to explore the therapeutic potential of Nrf2/ARE pathway activation in the context of CAG. We discuss the mechanisms underlying the activation of Nrf2, its role in regulating antioxidant genes, and its impact on oxidative stress management in the gastric mucosa. Recent advancements in pharmacological agents that activate the Nrf2 pathway, such as rhein and certain traditional Chinese medicines, are also highlighted. These interventions have demonstrated protective effects against oxidative stress, reduced inflammation, and promoted gastric mucosal healing. We, further, explore the potential clinical applications of Nrf2 activators in CAG treatment and the challenges in translating these findings into clinical practice. In addition, we outline future research directions aimed at optimizing Nrf2 activation strategies and exploring combination therapies to enhance therapeutic outcomes in CAG patients. The findings underscore the importance of targeting the Nrf2/ARE pathway as a promising strategy for managing oxidative stress-related gastric diseases.

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