The micro/nano pores in natural mineralized tissues can, to a certain extent, affect their responses to mechanical loading but are generally ignored in existing indentation analysis. In this study, we first examined the void volume fraction of sound and caries lesion enamels through micro-computed tomography (micro-CT). A Berkovich indentation study was then carried out to characterize the effect of porous microstructure on the mechanical behavior of the human enamels. The indentation tests were also modeled using the nonlinear finite element analysis technique to simulate indentation load-displacement curves, which showed reasonable agreement with the experimental measurements. From the simulation results, the extent of densification in the plastic zone was identified and the corresponding stress and contact pressure evolutions were quantified. Further, a conventional elastic-perfectly plastic material model without considering micropores was also developed to investigate the compaction effect of the porous structure. The simulation results reveal that conventional elastic perfect-plastic constitutive models become less reliable to model the mechanical behavior of carious lesion enamel with increasing loss of mineral content as it underestimates the yield stress and plastic energy dissipation. This study divulges the importance of compaction of porous enamel structure beneath the indented area. Note that understanding the effect of porous microstructures on plastic behavior is vital as the involved inelastic deformation mechanism associated with irreversible processes, such as wear and localized microcracking, has a significant bearing on wear and fatigue behavior of enamel. Statement of significanceBased on micro-CT and nano-indentation characterization, a numerical model was developed aiming to precisely describe the deformation behavior of naturally porous enamel. Inelastic properties and energy dissipation characteristics of porous enamel were investigated in detail. This work demonstrated that the existence of micro-pores in White Spot Lesions (WSLs) contributes to mechanical stability, which can mitigate the reduction in Young's modulus and fracture toughness resulting from loss of mineral components. The knowledge gained from this study can be used to explain the mechanisms related to irreversible processes, such as contact induced cracking and wear, and strengthen understanding of the mechanical behavior of porous mineralized tissues.