Aim: The aim of the current study was to appraise the efficiency of two different dentin biomodifiers on the shear bond strength of the dentin-resin interface. Materials and methods: A total of 60 human deciduous molars without dental caries were utilized for the purpose of this research. Individual teeth were subjected to mounting on self-curing acrylic resin, uncovering them 1 mm beneath the cementoenamel junction (CEJ). Preparation of class V cavities was performed on the buccal surface of the teeth with the occlusal edge in the enamel while the cervical borders were positioned 0.75 mm apical to the CEJ. After the cavity preparations were made using consistent proportions, the specimens were allocated at random to one of the three groups (n = 20)—the Group I—control group, Group II—casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), and group III—chitosan nanoparticles (CNPs). The universal single-bond adhesive system was subjected to application on the specimens. Each of the finished specimens was tested for its shear bond strength by employing the universal testing machine. Results: Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) group at 161.32 ± 5.220 showed the highest shear bond strength, in pursuit by the CNPs group at 158.18 ± 5.148 and finally, the control group at 124.98 ± 7.246. A statistically noteworthy dissimilarity was noted among the three groups. On multiple contrast assessments of dentin biomodifiers on shear bond strength, a greatly significant disparity was noted amid the control vs CPP-ACP and control vs CNPs (p < 0.001). Conclusion: Amid the confines of the limitations that this research had, it can be inferred that the utility of dentin biomodifiers like CPP-ACP as well as CNPs have the potential to improve the enduring steadiness of the dentin bond, thus improving the durability of the tooth-restoration composite. However, the CPP-ACP cohort exhibited somewhat improved shear bond strength vs CNPs. Clinical significance: Multiple dentin biomodifiers are presently accessible to decrease the degradation of collagen by enzymes as well as enhance their mechanical strength and steadiness. Biomodifying dentin utilizes inhibiting agents for matrix metalloproteinases (MMPs) in addition to the use of dentinal collagen cross-linkers. Such biomodification of dentin seems to be a competent move toward the stabilization of the resin-dentin bond.