BACKGROUND: Buruli ulcer (BU) can lead to disfiguring ulcers and permanent disability. The 2030 World Health Organization (WHO) road map for Neglected Tropical Diseases (NTDs) calls for major scaling up in diagnosis and management to eliminate disability due to the disease. Current treatment for BU is with daily oral rifampicin (10mg/kg dose) and clarithromycin (15mg/kg dose) for eight weeks, combined with standard gauze wound dressings. Dialkylcarbamoyl chloride (DACC)-coated dressings have been shown to irreversibly bind bacteria on wound surfaces resulting in their removal when dressings are changed. This trial aims to determine whether combining a high-dose oral rifampicin regimen with DACC dressings can improve the rate of wound healing relative to standard-dose oral rifampicin combined with DACC dressings. METHODS: This is an individual, multi-centre Phase 3 randomised controlled trial, which will be conducted in three clinical sites in Ghana. The primary outcome measure will be the mean time to clearance of viable mycobacteria. Cost and health-related quality of life data will be collected, and a cost-effectiveness analysis will be performed. DISCUSSION: The findings from this trial could lead to a change in how BU is treated. A shorter but more efficacious regimen would lead to improved treatment outcomes and potentially substantial financial and economic savings. TRIAL REGISTRATION: Pan African Clinical Trials Repository (registration number; PACTR202011867644311). Registered on 30 th November 2020.