IntroductionIrritable bowel syndrome (IBS) has high rates of psychiatric comorbidity, and impairs health-related quality of life (HRQL). Cognitive–behavioural therapy (CBT) is an effective treatment for IBS, but access to treatment remains low. Our proposed solution is a CBT-based smartphone app, Zemedy.Methods and analysisThis randomised controlled trial of Zemedy (V.2.0) uses an education and relaxation training active control app meant to simulate treatment as usual. A target N of 300 participants complete baseline questionnaires and consent at screening, and are then allocated to either the immediate treatment (Zemedy) or the active control. Treatment lasts 8 weeks, after which both groups complete the same battery used at baseline, and the control group is crossed over to Zemedy. After another 8 weeks, the crossed-over participants will be surveyed once more. Follow-up questionnaires are administered at 3, 6 and 12 months post-treatment. Primary outcomes include gastrointestinal symptom severity and HRQL. Clinically significant change will be defined as post-treatment scores falling within 2 SD of the healthy mean. Analysis will include intent-to-treat between-groups comparisons, controlling for baseline symptom severity, as well as moderation and mediation analyses. We hypothesise that the Zemedy app will outperform the active control app in reducing IBS symptom severity and improving HRQL.Ethics and disseminationThis study was approved by the Institutional Review Board at the University of Pennsylvania. Results will provide essential information on the efficacy and acceptability of an app-based CBT treatment for IBS. The data gathered may help establish the Zemedy app as an empirically supported intervention for IBS and will assist funding bodies in deciding whether to invest in its further development and dissemination. The results will be disseminated to patients with IBS via the media and the company website, to healthcare professionals via professional training (e.g. webinars and grand rounds talks) and to researchers via conferences and publications.Trial registration numberNCT04665271 (https://clinicaltrials.gov/ct2/show/NCT04665271).