Background: Irritable Bowel Syndrome (IBS) is a functional gastrointestinal disorder frequently accompanied by psychological disturbances such as depression and reduced quality of life. Probiotic intervention has been studied as a potential adjunct therapy to address psychological symptoms and improve the quality of life in IBS patients. This study aims to evaluate the effect of probiotic supplementation on depressive symptoms and quality of life in IBS patients at Dr. Cipto Mangunkusumo National General Hospital using the Beck Depression Inventory-II (BDI-II) and SF-36 instruments. Methods: This study was a double-blind randomized controlled trial with a pre-post intervention design. A total of 70 participants were randomly assigned into two groups: the intervention group (n=35), which received probiotics, and the control group (n=35), which received a placebo. Depressive symptoms were assessed using the BDI-II, while quality of life was measured using the SF-36 questionnaire, both before and after the intervention. Statistical analysis was performed using the Mann-Whitney test and independent t-test, with a significance level of p<0.05. Results: After the intervention, the probiotic group showed a significant reduction in BDI-II scores compared to the placebo group (p<0.0001). In addition, the probiotic group demonstrated significant improvements in almost all domains of the SF-36 compared to the placebo group, including physical functioning, role physical, bodily pain, general health, vitality, social functioning, emotional well-being, and mental health (p<0.0001). Conclusion: Probiotic supplementation significantly reduces depressive symptoms and improves quality of life in IBS patients. These findings support the potential of probiotics as an adjunct therapy in the comprehensive management of IBS. © 2025, Indonesian Society of Internal Medicine. All rights reserved.