The interfaces between organic and inorganic phases in natural materials have a significant effect on their mechanical properties. This work presents a quantification of the interface stress as a function of interface chemical changes (water, organic molecules) in chitin–calcite (CHI–CAL) interfaces using classical non-equilibrium molecular dynamics (NEMD) simulations and steered molecular dynamics (SMD) simulations. NEMD is used to investigate interface stress as a function of applied strain based on the virial stress formulation. SMD is used to understand interface separation mechanism and to calculate interfacial shear stress based on a viscoplastic interfacial sliding model. Analyses indicate that interfacial shear stress combined with shear viscosity can result in variations to the mechanical properties of the examined interfacial material systems. It is further verified with Kelvin–Voigt and Maxwell viscoelastic analytical models representing viscous interfaces and outer matrix. Further analyses show that overall mechanical deformation depends on maximization of interface shear strength in such materials. This work establishes lower and upper bounds of interface strength in the interfaces examined.