Substitution is an effective method to create new nonlinear optical (NLO) materials with an enhanced second harmonic generation (SHG) response. However, the large SHG enhancement caused by the substitution of Mg2+ for Zn2+ in an isostructural system is rare and has not been investigated yet. Here we elucidate the contribution of Zn2+ with d(10) electronic configuration to the SHG response based on two isostructural silicates Sr2MSi2O7 (M = Zn and Mg). The powder SHG measurements show that the SHG response of Sr2ZnSi2O7 is approximately 35 times that of alpha-SiO2 and 7 times higher than its isostructural compound Sr2MgSi2O7. The calculated band structures reveal that the difference in band gaps is minute and the sp hybridization between 4s-orbitals of Zn and 2p-orbitals of O is stronger than that between 3s-orbitals of Mg and 2p-orbitals of O. The significantly enhanced SHG response of Sr2ZnSi2O7 can be interpreted by the enhanced inter-band dipole resulting from strong sp hybridization between Zn and O. This provides a route to design new materials with enhanced NLO properties in the isostructural system.