Maintaining the stability of ecosystem functions to global change calls for a better understanding the regulatory factors of functionally specialized microbial-groups and their population-response to disturbance. Here, we explored this issue by collecting soils from 54 managed ecosystems in China and building a predictive model of microcosm experiments. Soil carbon:nitrogen:phosphorus (C:N:P) stoichiometry (35%~49%) imparted a greater individual effects on the abundances of microbial-groups associated with main carbon C, N, and P biogeochemical processes in comparison with geographical conditions (7%~10%). Soil total C and N contents were significantly positively correlated with the abundances of diazotrophs (nifH), nitrifiers (bacterial amoA), nitrate reducers (narG) and denitrifiers (nirS/K and nosZ genes). Soil C:N ratio not only exhibited a negative relationship with the abundances of P activators (phoD, phoC and pqqC genes), but also with cellulolytic decomposers (fungcbhIR and GH74 genes). Nitrogen cycling genes, including bacterial amoA, nirS, narG and norB, exhibited higher genetic resistance to N deposition compared with the drying-wetting cycles and warming. Soil total C, N and P contents, and their ratios had a strong direct effect on the genetic resistance of microbial-groups. Soil C:P ratio was selected by random forest analyses as the main predictor of N cycling genetic resistance to N deposition. Soil total C and N contents, and their ratios were the main predictors of the P cycling genetic resistance to three global change drivers. Overall, our work highlights the importance of soil stoichiometric balance for maintaining the ability of microbially-driven ecosystem functions to withstand global change.