Serpentine is widely distributed in the regolith and occurs in different types (chrysotile, lizardite, antigorite). The physical and chemical processes such as composition dissolution and structure evolution of serpentine occur constantly under the action of aqueous solutions. Based on the similarities and differences of polysomic structures and properties of chrysotile (tubular shapes) and lizardite (flat structural layers), the mineral–water interfacial reaction of these two minerals was carried out in a sulfuric acid solution with a concentration of 1 mol L–1. The mineral samples were characterized by powder X-ray diffraction, Fourier-transform infrared spectroscopy, scanning and transmission electron microscopy, Brunauer–Emmett–Teller surface area analysis, magic angle spinning nuclear magnetic resonance, and inductively coupled plasma mass spectrometry. The Si, Mg, and Fe dissolution concentrations, dissolution rates, and dissolution rules and structural changes of chrysotile and lizardite were studied and compared. The results show that H+ is more aggressive toward lizardite in sulfuric acid solution. The dissolution rate of Si, Mg, and Fe was faster, the dissolution concentration was greater, and structural changes occurred preferentially in lizardite. Specifically, Mg dissolved first in the octahedral sheets, and Si and Fe dissolved later in the tetrahedral sheets. After the water interfacial reaction with the sulfuric acid solution, the ion dissolution rates of both chrysotile and lizardite were Mg > Fe > Si. In summary, this work investigates the mineral–water interfacial reaction of chrysotile and lizardite in sulfuric acid media from different crystal structures and demonstrates that the crystal structure has a significant effect on the acid reactivity of lizardite minerals. Furthermore, the crystal chemistry patterns for the structural dissociation of different two-dimensional structural units were studied. This work provides a mineralogical basis for the study of the mechanisms of ion migration and crystal-structure evolution of serpentine under acidic media.