Properties of grain boundaries are pronouncedly influenced by alien elemental segregation. Synergistic effect of co-segregation behavior on mechanical properties of Mg {101̅2} twin grain boundary was systematically investigated with first-principles calculations. Ten elements (Ni, Mn, Zn, Al, Ag, Ti, Li, Zr, Y, Ca) for single segregation and four solute combinations (Al-Ca, Al-Y, Zn-Ca, Zn-Y) for co-segregation were chosen respectively, the segregation energies and solubility energies with different elemental concentrations were calculated to evaluate the thermodynamic stability of corresponding segregated grain boundaries. These solute atoms have unique effects on the stability of the system, and the interaction between solute atoms also has a synergistic effect on the stability of the system. It is found that the segregation tendency is enhanced and the grain boundary structure tends to be stable with the increase of the concentration of solute atoms at the appropriate sites, regardless of single-element segregation or co-segregation. The redistribution of grain boundary charges due to co-segregation significantly affects the binding and mechanical properties of grain boundaries. With the increase of the co-segregation concentration, the lamellar charge is transferred between the matrix and the twins, which further enhances the electron hybridization and leads to a notable enhancement of interface binding. This shows that the appropriate combination of solute elements can effectively improve the mechanical properties of the interface. The manuscript reveals the theoretical understanding of the effect of elemental segregation on the mechanical properties of grain boundary, and provides design ideas for the tuning of mechanical properties of magnesium alloy by grain boundary engineering.