Background: Irritable bowel syndrome (IBS) symptoms increase with aggravating psychological factors such as anxiety, mood disorders, depression, and stress caused by nerve stimulation. Effective psychotherapy-based interventions are essential for medical conditions and chronic diseases. Objectives: The present study aimed to investigate the effectiveness of cognitive-behavioral stress management (CBSM) for depression, anxiety, cognitive emotion regulation (CER), and quality of life (QoL) in IBS patients. Methods: This quasi-experimental study utilized a pretest-posttest design with a control group. The statistical population comprised all IBS patients visiting Be'sat Gastroenterology Specialist Clinic of Tehran in 2019. A sample of 50 patients was selected and randomly divided into intervention (CBSM, n = 25) and control (n = 25) groups. The experimental group underwent eight sessions (90-minute sessions per week) of CBSM, and the control group did not receive any intervention. The research instruments included the Cognitive Emotion Regulation Questionnaire (CERQ), the State-Trait Anxiety Inventory (STAI), the SF-36 Questionnaire (SF-36), and the Beck Depression Inventory (BDI-II). Multivariate analysis of covariance was used to analyze data. Results: The participants included 50 IBS patients aged 36.39 ± 7.45 years. The mean posttest scores for depression and anxiety were 24.70 ± 2.34 and 23.80 ± 2.88 in the experimental group and 29.73 ± 2.76 and 29.43 ± 2.77 in the control groups, respectively. The mean posttest score of QoL in the experimental group was 105.93 ± 7.85, which was significantly different from the control group score (92.03 ± 8.39). The CBSM was effective in reducing negative mood (depression and anxiety) and CER and improving QoL of IBS patients (P < 0.001). Conclusions: The CBSM is a practical therapeutic approach to increase QoL and reduce negative mood in IBS patients. Therefore, the CBSM can be used as an effective intervention to improve the QoL of IBS patients.