To achieve higher efficiencies and lower emissions, dual-fuel strategies have arisen as advanced engine technologies. In order to fully utilize engine fuels, understanding the combustion chemistry is urgently required. However, due to computation limitations, detailed kinetic models cannot be used in numerical engine simulations. As an alternative, approaches for developing reduced reaction mechanisms have been proposed. Nevertheless, existing simplified methods neglecting the real engine combustion processes, which is the ultimate goal of reduced mechanism. In this study, we propose a novel simplified approach based on fuel reactivity. The high-reactivity fuel undergoes pyrolysis first, followed by the pyrolysis and oxidation of the low-reactivity fuel. Therefore, the simplified mechanism consists of highly lumped reactions of high-reactivity fuel, radical reactions of low-reactivity fuel and C0-C2 core mechanisms. We have applied this methodology to a dual-fuel engine fueled with poly(oxymethylene) dimethyl ether 3 (PODE3) and ammonia. Species concentrations and ignition delay times have been used to validate our reaction mechanism. In conclusion, combustion chemistry simplification can be formulated by a reactivity-based approach. In the future, numerical simulations will be used to investigate the combustion characteristics of a PODE3/ammonia dual-fuel engine based on this method to optimize the combustion strategy.