Objective The objective of the study was to determine if zinc-doped etch-and-rinse dentin adhesive may induce therapeutic effects within the resin-dentin interface. Methods Human acid-etched dentin was infiltrated with Adper™ Single Bond Plus (SB, 3M ESPE, St. Paul, MN, USA), SB doped with 10 wt.% ZnO nanoparticles (ZnO-SB) or SB doped with 2 wt.% ZnCl2 (ZnCl2-SB). AFM/nanoindentation analysis was performed on fully hydrated specimens to evaluate the nanomechanical properties (Hi: hardness; Ei: modulus of elasticity) across the resin-dentin interface after different SBF storage periods (24 h, 1 m, 3 m). Confocal laser microscopy (CLSM) was used to evaluate the ultramorphology and micropermeability at 24 h and 3 m of SBF storage. Results SB control specimens exhibited a decrease in Hi in the hybrid layer (HL) and bottom of the hybrid layer (BHL) and a decrease in Ei in the HL after 3 m of SBF storage, indicating that severe degradation occurred in the control interface. ZnO-SB bonded specimens preserved the initial Hi and Ei at the HL and BHL subsequent SBF storage; ZnCl2-SB bonded specimens showed a decrease in Ei, in the HL over time. CLSM analysis confirmed that both Zn-doped adhesives were able to preserve the integrity of the HL. Significance Specific formulation of Zn-doped etch-and-rinse adhesives may offer the possibility to maintain the nano-mechanical properties along the dentin-bonded interface by inhibiting dentin MMPs and by protective mineral crystals formation within the resin-dentin interface. Clinical advantages may be expected by preserving and improving the integrity of the hybrid layer when Zn-doped adhesives are employed.