BACKGROUND: Oral rehydration therapy (ORT) is an effective and cheap treatment for diarrheal disease; globally, one of the leading causes of death in children under five. The World Health Organization launched a global campaign to improve ORT coverage in 1978, with activities such as educational campaigns, training health workers and the creation of designate programming. Despite these efforts, ORT coverage remains relatively low. The objective of this systematic review is to identify the barriers and facilitators to the implementation of oral rehydration therapy in low and middle-income countries. METHODS: A comprehensive search strategy comprised of relevant subject headings and keywords was executed in 5 databases including OVID Medline, OVID Embase, OVID HealthStar, Web of Science and Scopus. Eligible studies underwent quality assessment, and a directed content analysis approach to data extraction was conducted and aligned to the Consolidated Framework for Implementation Research (CFIR) to facilitate narrative synthesis. RESULTS: The search identified 1570 citations and following removal of duplicates as well as screening according to our inclusion/exclusion criteria, 55 articles were eligible for inclusion in the review. Twenty-three countries were represented in this review, with India, Bangladesh, Egypt, Nigeria, and South Africa having the most representation of available studies. Study dates ranged from 1981 to 2020. Overarching thematic areas spanning the barriers and facilitators that were identified included: availability and accessibility, knowledge, partnership engagement, and design and acceptability. CONCLUSION: A systematic review of studies on implementation of ORT in low- and middle-income countries (LMICs) highlights key activities that facilitate the development of successful implementation that include: (1) availability and accessibility of ORT, (2) awareness and education among communities, (3) strong partnership engagement strategies, and (4) adaptable design to enhance acceptability. The barriers and facilitators identified under the CIFR domains can be used to build knowledge on how to adapt ORT to national and local settings and contribute to a better understanding on the implementation and use of ORT in LMICs. The prospects for scaling and sustaining ORT (after years of low use) will increase if implementation research informs local applications, and implementers engage appropriate stakeholders and test assumptions around localized theories of change from interventions to expected outcomes. REGISTRATION: A protocol for this systematic review was developed and uploaded onto the PROSPERO international prospective register of systematic reviews database (Registration number: CRD420201695).