IntroductionThere has no consensus on optimal management of carpal tunnel syndrome (CTS), the most common compression neuropathy. Conservative therapy is generally accepted as first-line intervention. Therapeutic ultrasound has been widely reported to be treatment beneficial in nerve regeneration and conduction, and further accelerate compression recovery. The purpose of this study is to investigate the effectiveness of therapeutic ultrasound for CTS treatment.Methods and analysisThis study protocol entails a three-arm, prospective, multicentre, randomised controlled trial. 162 eligible adult participants diagnosed with mild to moderate CTS by using criteria developed from a consensus survey by the UK Primary Care Rheumatology Society will be assigned to either (1) therapeutic ultrasound, (2) night splint or (3) therapeutic ultrasound +night splint (combined) group. Primary outcome will be difference in Symptom Severity Scale of Boston Carpal Tunnel Questionnaire (BCTQ-SSS) at 6-week between night splint and therapeutic ultrasound +night splint groups. Secondary outcomes include Functional Status Scale of BCTQ, sleep questionnaire for interrupted sleep, EuroQol-5D for general health, Hospital Anxiety and Depression Scale for mental status, Work Limitations Questionnaire-25 for functional limitations at work, Global Rating of Change for treatment success and recurrence rate, physical examination, electrophysiological and ultrasound parameters. Intention-to-treat analyses will be used.Ethics and disseminationEthics committees of all clinical centres have approved this study. The leading centre is Shanghai Sixth People’s Hospital, whose approval number is 2021-152. New versions with appropriate amendments will be submitted to the committee for further approval. Final results will be published in peer-reviewed journals and presented at local, national and international conferences.Trial registration numberChiCTR2100050701.