With outstanding photoelectric properties, organic-inorganic perovskites have become promising materials in the application of solar cells. However, their low stability limits their high conversion efficiency. On the basis of first-principles calculations, we screened out the optimal dopant into MAPbI3 from a variety of organic cations, and further revealed the mechanism underneath for the improved stability of cations doping. Our results have demonstrated that the doping of large-size cations (i.e., IPA+, TriMA+, and GA+) could efficiently inhibit the formation and diffusion of structural defects with high defect formation energies and large migration barriers, which is associated with the lattice expansion and greater hydrogen-bond formation. Our theoretical findings address crucial guidelines to design and synthesize the organic-inorganic perovskite materials with high stability, and provide valuable insights in understanding the stability mechanism, which may enhance the photovoltaic efficiency of perovskite materials and extend their wide applications.