This study aimed to investigate the efficacy and durability of bioactive glass-based dental resin infiltrants. Resin infiltrants were formulated by combining photoinitiated dimethacrylate monomers with three variations of bioactive glass: 45S5 Bioglass (RIS), boron-substituted (RIB), fluoride-substituted (RIF), and pure resins (PR), whereby TOOTH group (TH) and ICON (CN) served as commercial control groups. Teeth samples were prepared, and experimental and control infiltrants were applied on demineralized human-extracted teeth. All the samples were subjected to immersion in artificial saliva and pH cycling for 30 days. The samples from another group underwent tooth brushing simulation for 9600 cycles. Following artificial saliva immersion, the samples' hardness values showed that RIB had the highest values (318.44 ± 3.83) while PR (212.52 ± 9.02) had the lowest values. After immersing into the pH cycling solution, the RIF showed the highest hardness (286.86 ± 5.11), while the lowest values for the CN (143.76 ± 3.50). After the tooth brushing simulation, the teeth samples with RIB showed maximum microhardness values (312.06 ± 16.30) and the weakest for the TH (189.60 ± 6.43). The commercial and experimental enamel resin infiltrants showed almost similar results overall, with RIB demonstrating better microhardness and comparable surface roughness. In contrast, RIF proved more resistant to pH cycling, exhibited higher microhardness, and performed better in surface roughness analysis. These findings suggest that resin infiltrant materials, especially RIF, have promising potential for effectively and esthetically managing white spot lesions.