Objective: To explore the clinical effect and safety of mosapride combined with Bacillus licheniformis in patients with constipation irritable bowel syndrome (IBS-C). Methods: A total of 126 patients with IBS-C admitted to Lianyungang Second People’s Hospital from January 2017 to December 2021 were selected and divided into an observation group (n=93) and a control group (n=33) according to different treatment methods. The control group was treated with mosapride, and the observation group was treated with mosapride combined with Bacillus licheniformis. The clinical efficacy, intestinal flora, and safety of the 2 groups were compared. Results: The total effective rate of the observation group (89.25%) was significantly higher than that of the control group (72.73%), and the difference between the 2 groups was significant (P<0.05). After the treatment, E. coli decreased and Lactobacillus increased in both groups (P<0.05), and E. coli in the observation group was lower than that in the control group and Lactobacillus was higher than that in the control group (P<0.05). Before the treatment, there was no significant difference in clinical symptoms between the 2 groups (P>0.05). After the treatment, the main defecation frequency, defecation difficulty, abdominal distension, abdominal pain, and incomplete defecation in the observation group were not all better than those in the control group (all P<0.05). After the treatment, the resting pressure and maximum compression pressure of the anal canal in the observation group were significantly higher than those in the control group, and the rectal perception range, the maximum tolerance of the rectum, and the rectal anal inhibitory reflex were significantly lower than those in the control group (all P<0.05). There was no significant difference in the incidence of adverse reactions between the 2 groups (P>0.05). Conclusion: The treatment of IBS-C patients with mosapride combined with Bacillus licheniformis can improve the clinical efficacy, improve the clinical symptoms and anorectal motility index of the patients, regulate the intestinal flora of the patients, and have high safety, which is worthy of clinical promotion.