Background <p>There have been limited previous reviews on the use of sealants in high-caries-risk children that include multiple study designs. This systematic review aimed to evaluate the preventive effect of sealants on high-caries-risk children and compare the effectiveness of sealants between high-caries-risk children and lower-caries-risk children.</p> Methods <p>An initial protocol was developed following the PRISMA guidelines. A comprehensive literature search was performed across several electronic databases, including PubMed, the Cochrane Library, Embase and Google Scholar. Experimental or observational studies that examined resin-based sealants for preventing caries over at least 12 months in high-caries-risk children, identified by individual risk assessment, were included. Comparison groups were moderate- or low-risk children or no sealant; if unavailable, only intervention data were used. The risk of bias was assessed via the RoB2 tool and the Newcastle‒Ottawa Scale.</p> Results <p>A total of 1651 unique records were identified, 20 of which were included in this systematic review. Studies comparing only sealed teeth among different caries risk groups have indicated that high-caries-risk children have a greater risk of developing new carious lesions than low- or moderate-risk children do. In contrast, the effect of sealants was negligible in low-caries-risk children when compared between sealed and nonsealed teeth. Additionally, caries experience was the primary criterion used across all included studies.</p> Conclusion <p>Resin-based sealants are still recommended for high-caries-risk children. However, generalizability and an appropriate threshold for risk assessment remain unclear owing to the limited number of studies from low- to middle-income countries and variability in risk assessment methods.</p> Systematic review registration <p>PROSPERO Registration number CRD42023473013.</p> Clinical trial number <p>Not applicable.</p>