Due to the complexity of the oral environment, understanding the relationship between the enamel microstructure and corrosion behavior of mammalian teeth is important for the development and bionic design of novel dental materials with corrosion resistance. In this paper, enamel microstructure and its influence on corrosion and tribocorrosion behavior of bovine and human molars are studied using focused ion beam & scanning electronic microscopy (FIB-SEM), transmission electron microscope (TEM), nanoindentation, and wear testing. It was found that the regions with transversal HAP nanocrystallites have better corrosion resistance than those with longitudinal crystallites. Apart from the chemical composition, the microstructure of enamel also involves in its surface corrosion. HAP nanocrystallite orientation changes the acid permeability into the enamel surface. Transversal nanocrystallites result in zigzagged acid permeation channels to increase the difficulty of acid penetration and then improve the corrosion resistance of enamel surface. The higher the fraction of transversal nanocrystallites on a surface, the better is the corrosion resistance. These findings extend our understanding of the corrosion/wear mechanisms of dental enamel with different microstructures.