In the automotive industry, hydrogen (H2) fueled engines are nowadays gaining increasing attention as promising technology for the upcoming CO₂-neutral environment scenario, especially for commercial vehicle applications. In this framework, H2 direct-injection (DI) systems play a key role in the development of suitable mixture preparation mechanisms aiming at meeting the power and torque targets set by the hydrocarbons fueled engines. To this purpose, the many degrees of freedom allowed by the H2-DI systems such as e.g., injector position and geometry as well as injection pressure and timing, can be successfully used to promote the mixture formation, for a given intake ports configuration and depending on the combustion chamber geometry. Thus, the challenge of the combustion system development resides in providing the optimal combination of jet targeting and injection strategy over the whole engine map. This paper suggests a combined numerical and experimental approach aiming at disclosing the effects of the jet-charge motion interaction provided by the H2-DI injection system integrated in an originally NG-fueled single cylinder engine (SCE). Different intake port designs, allowing for increasing swirl levels, have herein been simulated by means of 3D CFD U-RANS and subsequently tested on the thermodynamic SCE for establishing a correlation between in-cylinder mixing processes and engine test bench results. The obtained characterization of the engine behavior is extended to DI-operation strategy variations for further improvement of engine-out emissions and performance of the adopted combustion system.