Objective To explore the effect of Shenling Baizhu Powder and moxibustion on serum brain-gut peptide in patients with diarrhea predominant irritable bowel syndrome (D-IBS). Methods Sixty D-IBS cases were randomly divided into two groups, 30 cases in the treatment group were given Shenling Baizhu Powder and moxibustion therapy, and 30 patients in the control group were given loperamide hydrochloride capsule. Treatment for the two groups lasted for 4 weeks. Clinical symptoms and serum brain gut peptide (5-HT, VIP and SP) levels of two groups were observed before and after treatment, clinical efficacy were evaluated. Results Markedly effective rate of the treatment group was 66.7% (20/30), better than 33.3% (10/30) in the control group (P<0.05). After treatment, clinical symptom scores of the treatment group decreased significantly (P<0.01), while only diarrhea and abdominal pain improved in the control group (P<0.01), with statistical significance (P<0.01). After treatment, serum 5-HT, VIP, and SP of the treatment group were decreased (P<0.01), while these indexes of the control group did not change significantly (P>0.05), with statistical significance (P<0.01). Conclusion Clinical efficacy of Shenling Baizhu Powder and moxibustion in treating D-IBS is better than that of loperamide hydrochloride capsule, and can significantly improve clinical symptoms and regulate serum brain-gut peptides levels.