To determine the efficacy of trimebutine maleate combined with hyperbaric oxygen therapy on irritable bowel syndrome. Totally 180 patients diagnosed as irritable bowel syndrome who were admitted to our hospital between June 2016 and June 2019 were enrolled and randomized into the control group and the observation group according to the number of visits (each n=90). The control group was treated with trimebutine maleate through oral medication, while the observation group was given hyperbaric oxygen therapy additionally based on the treatment for the control group. Both groups were treated for 4 w. Then the following items of the two groups before and after intervention were evaluated and compared: serum neurotransmitter-associated parameters (5-hydroxytryptamine, somatostatin, substance P, neuropeptide Y), rectal manometry parameters (rectal sensation threshold, rectal defecation threshold, rectal pain threshold and rectal motor index), self-rating anxiety scale score and efficacy. Before treatment, no notable difference was found between the two groups in rectal manometry indices, serum neurotransmitter-associated indices and self-rating anxiety scale score (all p>0.05). After treatment, the rectal manometry indices, serum neurotransmitter-associated indices and self-rating anxiety scale score of both groups were greatly improved (all p<0.05) and all these improvements in the observation group were more significant than those in the control group (all p<0.05). In addition, the observation group got notably higher efficacy than the control group (p<0.01). Trimebutine maleate combined with hyperbaric oxygen therapy is effective in the therapy of irritable bowel syndrome, without toxic and side effects, so it is worthy of clinical application.