Aim: Biodegradation of collagen matrix is one of the main factors in reducing the strength of dentin–resin bond over time. The present study aimed to evaluate the effect of four natural agents on the prevention of collagen degradation which increases bond strength. Materials and methods: Twenty-five sound human premolars were selected. The middle one-third of the dentin was exposed by removing occlusal part of the crown. In order to increase the bond strength of the dentin–resin interface, four collagen cross-linking agents and matrix metalloproteinase (MMP) inhibitors were used in this study. The teeth were randomly divided into five groups according to the dentin treatment; control group (no treatment), pretreatment with chlorhexidine (CHX), grape seed extract (GSE), omega-9, and omega-6, respectively. Teeth were restored with Tetric N-Bond adhesive system and resin composite. After thermocycling, all the specimens were mounted on the slicing machine and then sectioned to produce a 1.0 mm² cross-sectional surface area that tested for tensile bond strength. Data were analyzed using one-way analysis of variance (ANOVA) and post hoc Tukey test. Results: The CHX pretreatment group (36.45 ± 1.85 MPa) had a significantly higher bond strength, compared to the other groups (p 0.05). Conclusion: The application of natural collagen cross-linkers and MMP inhibitors in this study (CHX 2%, GSE 6.5%, omega-9, and omega-6) were capable of significantly increasing resin–dentin bond strength.