Strict regulations and legislation for carbon emissions and pollution from heavy-duty engines are pushing towards carbon-free fuels such as hydrogen as a fuel for internal combustion engines. Moving towards this goal, the engine design needs to fully comply with hydrogen’s unique characteristics to achieve optimum performance and efficiency. One aspect that can potentially improve combustion efficiency and emissions is adopting the pre-chamber ignition strategy in large-bore engines at lean conditions. The pre-chamber is a small cavity, usually 3-6% of the total engine volume, installed on the cylinder head, housing the initial combustion event, which would then inject the turbulent jet into the main chamber via nozzles placed at the bottom of the pre-chamber. This ignition strategy would provide multiple flame fronts into the main chamber, accelerating combustion speed and enhancing engine performance. However, the pre-chamber must be designed specifically for Hydrogen combustion to make the best use of this strategy. In this paper, we aimed to investigate the effects of pre-chamber designs such as pre-chamber dome, pre-chamber volume and nozzle diameter on the combustion development in the pre-chamber and, consequently, the combustion in the main chamber along with the engine performance and efficiency of a 2 L single-cylinder heavy-duty hydrogen engine. The simulations are performed in Star-CD software. This research shows that an optimum pre-chamber configuration can significantly affect engine performance. The nozzle diameter has a non-monotonic effect on the jetting propagation. Specifically, a small nozzle diameter will slow down the flame development inside the pre-chamber, followed by restricting the ejected flame jets, while a wider nozzle diameter will weaken the jet momentum into the main chamber. Further, the results revealed that increasing the pre-chamber volume largely enhanced the performance and combustion development, resulting in significant improvements to overall engine performance. Thus, it is clear that the optimum pre-chamber design configuration could significantly improve thermal efficiency, and the dedicated pre-chamber design is critical to achieving optimal performance.