Background: Diarrhoeal disease remains a common cause of illness and death in children <5 years of age. Faecal-oral infection by Shigella spp. causing bacillary dysentery is a leading cause of moderate-to-severe diarrhoea, particularly in low and middle-income countries. In Southeast Asia, S. sonnei predominates and infections are frequently resistant to first-line treatment with the fluoroquinolone, ciprofloxacin. While resistance to all antimicrobials is increasing, there may be theoretical and clinical benefits to prioritizing treatment of bacillary dysentery with the azalide, azithromycin. In this study we aim to measure the efficacy of treatment with azithromycin compared with ciprofloxacin, the current standard of care, for the treatment of children with bacillary dysentery. Methods and analysis: We will perform a multicentre, open-label, randomized controlled trial of two therapeutic options for the antimicrobial treatment of children hospitalised with dysentery. Children (6–60 months of age) presenting with symptoms and signs of dysentery at Children’s Hospital 2 in Ho Chi Minh City will be randomised (1:1) to treatment with either oral ciprofloxacin (15mg/kg/twice daily for 3 days, standard-of-care) or oral azithromycin (10mg/kg/daily for 3 days). The primary endpoint will be the proportion of treatment failure (defined by clinical and microbiological parameters) by day 28 (+3 days) and will be compared between study arms by logistic regression modelling using treatment allocation as the main variable. Ethics and dissemination: The study protocol (version 1.2 dated 27th December 2018) has been approved by the Oxford Tropical Research Ethics Committee (47–18) and the ethical review boards of Children's Hospital 2 (1341/NĐ2-CĐT). The study has also been approved by the Vietnamese Ministry of Health (5044/QĐ-BYT). Trial registration: Clinicaltrials.gov: NCT03854929 (February 26th 2019).