Hydrogen and its unique properties pose major challenges to the development of innovative combustion engines, while it represents a viable alternative when it is based on renewable energy sources. The present paper deals with the holistic approach of hydrogen combustion modeling from a 0D/1D reactor evaluation with Cantera up to complete engine simulations in the 3D-CFD tool QuickSim. The obtained results are referenced to the current literature and calibrated with experimental data. In particular, the engine simulations are validated against measurements of a single-cylinder research engine, which was specifically adapted for lean hydrogen operation and equipped with port fuel injection and a passive pre-chamber system. Special attention is hereby given to the influence of different engine loads and varying lambda operation. The focus of this work is the complementary numerical investigation of the hydrogen flame speed and its self-ignition resistance under the consideration of various reaction mechanisms. A detailed transfer from laminar propagation under laboratory conditions to turbulent flame development within the single-cylinder engine is hereby carried out. It is found that the relatively simple reaction kinetics of hydrogen can lead to acceptable results for all mechanisms, but there are particular effects with regard to the engine behavior. The laminar flame speed and induction time vary greatly with the inner cylinder conditions and significantly affect the entire engine’s operation. The 3D-CFD environment offers the opportunity to analyze the interactions between mixture formation and combustion progress, which are indispensable to evaluate advanced operating strategies and optimize the performance and efficiency, as well as the reliability, of the engine.