BackgroundDental caries is the most prominent childhood disease in the world. In the United States, more than 50% of children have experienced caries. Untreated caries can have negative impacts on quality of life, academic performance, and school attendance. To reduce oral health disparities, multiple organizations recommend school-based caries prevention.Methods/designA longitudinal, cluster randomized, non-inferiority trial will be conducted in low-income children from primarily Hispanic/Latino backgrounds currently enrolled in public elementary schools in New York City, New York, United States, from 2018 to 2023. The primary objective is to compare the non-inferiority of silver diamine fluoride and fluoride varnish versus glass ionomer therapeutic sealants and fluoride varnish in the arrest and prevention of dental caries. Secondary objectives are to evaluate differences in effectiveness when care is provided by nurses versus dental hygienists and assess the impact of prevention on oral health-related quality of life and educational outcomes. Caries arrest will be evaluated after 2 years, and caries prevention and secondary outcomes will be assessed at the completion of the study. Data analysis will follow intent-to-treat, and statistical analyses will be conducted using a two-sided significance level of 0.05.DiscussionThe comparative effectiveness of alternative caries prevention delivery models is considered to be one of the highest research priorities in the United States. Many treatments are currently available to prevent and arrest dental caries. The simplicity and affordability of silver diamine fluoride may be a viable alternative for the prevention of dental caries in high-risk children.Trial registrationU.S. National Library of Medicine, www.clinicaltrials.gov, ID: NCT03442309. Registered on 22 February 2018.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2891-1) contains supplementary material, which is available to authorized users.