In this work, the influence of the chemical composition (species and number of trivalent substitution atoms) on the acidity of the isomorphously substituted MCM-22 zeolite was investigated in detail by density functional theory. By calculating the proton affinity and NH3 adsorption energy, it was found that the acidity of the MCM-22 zeolite decreased with increasing number of trivalent substitution atoms introduced into the zeolite framework. Moreover, the acidity of the substituted MCM-22 increased in the sequence of B-MCM-22 < Fe-MCM-22 < Al-MCM-22, independent of the number of trivalent substitution atoms. The calculation results also showed that when Fe or B elements were incorporated into the framework of the aluminosilicate MCM-22 zeolite, the proton affinity of MCM-22 zeolite decreased in the order of B-MCM-22 > [Al,B]-MCM-22 > Fe-MCM-22 > [Al,Fe]-MCM-22 > Al-MCM-22. All these results were in good agreement with the experimental results.