Given the need to achieve the “EU Green Deal” targets, with net-zero Global Greenhouse Gas and neutral CO2 emissions in 2050, always more restrictive regulations have increased the interest of the automotive industries in sustainable and efficient Internal Combustion Engines (ICE) design. Especially in Heavy-Duty engines, Natural Gas (NG) became more and more attractive as alternative fuel, reducing adverse health effects of air pollution and, at the same time, ensuring high performance. As a result, the use of predictive numerical models has become necessary to support the experimental campaign, exploring multiple engine operating conditions and offering an important contribution in time-to-market reduction.