This study compared resin-based and glass ionomer sealants with regard to their fluoride-release behavior and anti-demineralization potential on adjacent unsealed enamel surfaces. Sealant cavities prepared on bovine enamel blocks were filled with fluoride-containing resin sealants [TeethmateF-1 (TF), Clinpro TM (CP)], and glass ionomer sealant [Fuji VII (FVII)]. Specimens were then incubated in artificial saliva for 14 days to measure fluoride. Thereafter, demineralization was performed for 10 days, and the anti-demineralization efficacy was assessed by Swept Source Optical Coherence Tomography (SS-OCT), and cross-sectional nanohardness. All data were statistically analyzed by using ANOVA. FVII exhibited the highest fluoride release. SS-OCT and nanohardness findings indicated that anti-demineralization efficacy of TF was the greatest, whereas FVII was not significantly different from that of CP. Resin sealants released a lower amount of fluoride but exhibited anti-demineralization effects on the adjacent unsealed enamel surfaces that were comparable to that of a glass ionomer sealant.