The performance of existing detailed chemical mechanisms with respect to moderate or intense low-oxygen dilution (MILD) combustion is not optimal. The use of optimization procedures can therefore be used to quantify and minimize the uncertainties in chemical mechanisms with respect to available experimental targets in these conditions. This work puts forth a methodology that improves the performance of chemical kinetics with respect to MILD combustion. The experimental data used in this paper are from a plug flow reactor, where the ignition delay time for methane and biomass pyrolysis products in MILD conditions was analyzed. The initial mechanism was then evaluated, and the reactions with the highest impact factors were used in the optimization process. The combination of parameters that gave the lowest error with respect to the experimental data was then determined, and the proposed mechanism performance was improved with respect to the experimental targets.