The focus of the current research is the selection of fuels used in a dual-fuel engine. These engines have received a great deal of attention in recent years because they can offer high thermal efficiency together with reduced emissions. Natural gas (NG) is the first choice for an alternative engine fuel because of its advantages of environmental friendliness, large energy storage capacity, and good economics. Polymethoxy dimethyl ether (PODE) with a high cetane number and low soot emissions is deemed to be one of the promising fuels or additives for direct injection compression ignition engines. Therefore, this study constructs the 124-species and 650-reaction PODE3/NG reduced mechanism for dual-fuel engine application. First, the PODE3 detailed mechanism was reduced under a wide range of enginelike conditions (the initial pressures were 10 and 15 bar, the equivalence ratios were 0.5-1.5, and the initial temperatures were 600-1400 K) by using the reduced methods of direct relation graph (DRG), directed relation graph with error propagation (DRGEP), rate of production (ROP), and sensitivity analysis (SA). Then, the NG reduced mechanism established by our research group was combined with the reduced PODE3 mechanism to develop the final PODE3/NG dual-fuel mechanism. The key chemical kinetic parameters of the combined mechanism were optimized by using SA. This optimized mechanism was evaluated using uncertainty analysis based on polynomial chaos expansions. Finally, the modeled dual-fuel mechanism behavior was subjected to extensive experimental verification for ignition delays, species profiles, and laminar flame speeds. The rate constants of key reactions related to H2O2 and methyl (CH3-) were improved so that the predicted values of laminar flame speed at high-pressure lean-burn conditions agreed well with the experimental data, and the improved mechanism does not affect the species concentration and ignition delay. In addition, since the construction of the reduced mechanism is a relatively compact model, it can be coupled with CFD for numerical simulation of dual-fuel engines.