Purpose Secondary caries originate from a leakage pathway where oral acids can penetrate faster and demineralize the tooth substrate deeper which can be visualized by dye penetration. The ability to prevent secondary caries by contemporary adhesive systems was evaluated in this study. Dye penetration distance through leakage and into the tooth substrate adjacent to Class V restorations after artificial caries exposure was compared. Materials and Methods Previously frozen extracted human molars were used to prepare the Class V cavities at the CEJ on axial surfaces. All cavities were restored with either the resin-composite or amalgam with or without resin adhesives: dry bonding: Super-Bond D-Liner II Plus; moist bonding: All-Bond 2; and self-etch bonding: AQ Bond and Clearfil Protect Bond. Two subgroups of Super-Bond D-Liner II Plus were immersed for 14 days at 37°C either in artificial saliva (negative control) or the artificial caries solution. The other groups were soaked in the artificial caries solution. The distance of dye penetration into the adjacent enamel, cementum/dentin, and tooth-resin interfaces was measured after immersion in 0.5% basic fuchsin dye for 24 h. The tooth-resin interfacial layer was investigated using SEM. Results No dye penetration into the tooth-resin interface was found in Super-Bond D-Liner II Plus and AQ Bond groups which demonstrated a constant hybrid layer after a chemical challenge. The leakage distance at the cementum/dentin-resin interface of All-Bond 2, Clearfil Protect Bond, and non-adhesive amalgam (positive control) groups was significantly higher than the distance of dye penetration into the adjacent demineralized root surface (p < 0.05). Conclusion Caries associated with either amalgam or resin-composite restorations can be prevented using resin adhesives which can penetrate into the intact tooth substrate to form a stable hybrid layer. With caries-free restorations, tooth vitality may be conserved lifelong.