Chronic stress causes duodenal damage, in which iron death is likely to play an important role. Chlorogenic acid (CGA), one of the most widely consumed dietary polyphenols, has been shown to protect the intestine. However, it is unclear whether CGA exerts a duodenoprotective effect in chronic stress by inhibiting ferroptosis. In this work, rats were daily exposed to restraint stress for 6 h over 21 consecutive days, with/without CGA (100 mg/kg, gavage). CGA reduced blood hepcidin, iron, reactive oxygen species (ROS), and ferroportin 1 (FPN1) levels and upregulated the levels of ferroptosis-related biomarkers (GPX4, GSH, NADPH, etc.). These results confirmed that CGA inhibited ferroptosis in the duodenum. Furthermore, the use of S3I-201 (STAT3 inhibitor) helped to further clarify the mechanism of action of CGA. Overall, CGA could reduce hepcidin production by inhibiting the IL-6/JAK2/STAT3 pathway in the liver to increase the expression of FPN1 in the duodenum, which restored iron homeostasis and inhibited ferroptosis, alleviating chronic stress-induced duodenal injury.