Background <p>Irritable bowel syndrome (IBS) is one of the most common brain–gut interaction disorders, characterized by chronic abdominal pain, altered bowel habits, and heightened stress responses that significantly affect patients’ psychological functioning and quality of life. Given that chronic stress plays a central role in the onset and maintenance of IBS symptoms, identifying psychological resources that promote adaptation and well-being is crucial. The present study aimed to examine the mediating role of resilience in the relationship between cognitive flexibility and psychological well-being among patients with IBS.</p> Method <p>This descriptive-correlational study employed a structural equation modeling approach. The statistical population included all IBS patients who referred to the Gastrointestinal Health Center at Al-Zahra Hospital in Isfahan in 2024. A sample of 300 patients was selected using convenience sampling. Data were collected using the Psychological Well-Being Scale, Cognitive Flexibility Inventory, and Connor–Davidson Resilience Scale, and analyzed using SPSS and AMOS version 28. </p> Findings <p>Results showed that cognitive flexibility and resilience significantly predicted psychological well-being, and that resilience mediated the relationship between cognitive flexibility and psychological well-being. These findings highlight the importance of resilience and cognitive flexibility as protective psychological resources that help patients manage stress and improve well-being in the context of IBS.</p>