INTRODUCTION: Antibiotic resistance endangers effective prevention and treatment of infections, and places significant burden on patients, families, communities and healthcare systems. Low-income and middle-income countries (LMICs) are especially vulnerable to antibiotic resistance, owing to high infectious disease burden, and limited resources for treatment. High prevalence of antibiotic prescription and use due to lack of provider's knowledge, prescriber's habits and perceived patient needs further exacerbate the situation. Interventions implemented to address the inappropriate prescription and use of antibiotics in LMICs must address different determinants of antibiotic resistance through sustainable and scalable interventions. The aim of this protocol is to provide a comprehensive overview of the methods that will be used to identify and appraise evidence on the effectiveness and cost-effectiveness of behaviour change interventions implemented in LMICs to improve the prescription and use of antibiotics. METHODS AND ANALYSIS: Two databases (Web of Science and PubMed) will be searched based on a strategy developed in consultation with an essential medicines and health systems researcher. Additional studies will be identified using the same search strategy in Google Scholar. To be included, a study must describe a behaviour change intervention and use an experimental design to estimate effectiveness and/or cost-effectiveness in an LMIC. Following systematic screening of titles, abstracts and keywords, and full-text appraisal, data will be extracted using a customised extraction form. Studies will be categorised by type of behaviour change intervention and experimental design. A meta-analysis or narrative synthesis will be conducted as appropriate, along with an appraisal of quality of studies using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) checklist. ETHICS AND DISSEMINATION: No individual patient data are used, so ethical approval is not required. The systematic review will be disseminated in a peer-reviewed journal and presented at a relevant international conference. PROSPERO REGISTRATION NUMBER: CRD42017075596.