Syngas from biomass gasification represents an interesting alternative to traditional fuels in spark-ignition (SI) internal combustion engines (ICEs). The presence of inert species in the syngas (H2O, CO2, N2) reduces the amount of primary energy that can be exploited through combustion, but it can also have an insulating effect on the cylinder walls, increasing the average combustion temperature and reducing heat losses. A predictive numerical approach is here proposed to derive hints related to the possible optimization of the syngas-engine coupling and to balance at the best the opposite effects taking place during the energy conversion process. A three-dimensional (3D) computational fluid dynamics (CFD) model is developed, based on a detailed kinetic mechanism of combustion, to reproduce the combustion cycle of a cogenerative engine fueled by syngas deriving from the gasification of different feedstocks. Numerical results are validated with respect to experimental measurements made under real operation. Main findings reveal how heat transfer mainly occurs through the chamber and piston walls up to 50° after top dead center (ATDC), with the presence of inert gases (mostly N2) which decrease the syngas lower calorific value but have a beneficial insulating effect along the liner walls. However, the overall conversion efficiency of the biomass-to-ICE chain is mostly favored by high-quality syngas from biomasses with low-ashes content.