Objective: To evaluate the therapeutic effect of Shu Gan Jian Pi Yi Qi prescription combined with grain-sized moxibustion on diarrhea-predominant irritable bowel syndrome (IBS-D) with liver depression and spleen deficiency syndrome. Methods: 60 patients with IBS-D (liver depression and spleen deficiency syndrome) treated in the outpatient clinic from January 2021 to December 2023 were selected and randomly divided into two groups using a random number table. The combined group was treated with Shu Gan Jian Pi Yi Qi prescription and grain-sized moxibustion, while the reference group was treated with western medication. The total effective rate, IBS symptom severity score (IBS-SSS), Bristol stool scale score, and IBS-specific quality of life questionnaire (IBSQOL) were compared between the two groups. Results: The total effective rate of the combined group was higher than that of the reference group (P < 0.05). Before treatment, there were no differences in IBS-SSS score, Bristol stool scale score, and IBSQOL score between the two groups (P > 0.05). After treatment, the IBS-SSS score and Bristol stool scale score of the combined group were lower than those of the reference group, while the IBSQOL score was higher (P < 0.05). Conclusion: Shu Gan Jian Pi Yi Qi prescription combined with grain-sized moxibustion can improve the symptoms of IBS-D patients, including stool characteristics, and enhance their quality of life.