Class 8 trucks are major contributors to greenhouse gas (GHG) emissions from heavy-duty vehicles (HDVs), responsible for about 50% of HDV-related emissions in the United States and 40% in Canada. While many studies have explored GHG reduction strategies, most focus on conventional diesel fuel. Pilot-ignited high-pressure direct injection (HPDI) of natural gas (NG) and hydrogen (H2) has shown potential in lowering pollutants and GHG emissions compared to diesel. This thesis assesses the combined effects of NG HPDI engines and hybrid-electric powertrains, as well as H2 HPDI engines, on GHG mitigation in a heavy-duty truck. A phenomenological combustion model was developed in GT-SUITE™ to simulate HPDI combustion and coupled with a machine learning model to capture methane (CH4) emissions. The framework was then adapted for hydrogen fueling within the same engine platform. Scaling studies were conducted to generate downsized variants suitable for hybrid architectures. Following this, the HPDI engine was optimized through adjustments to key parameters, such as compression ratio and injection timing, and the integration of advanced technologies, including turbo-compounding. The optimized engines were then evaluated in P2 parallel and plug-in hybrid vehicle models developed in Autonomie® by the University of Alberta team to demonstrate their efficiency benefits and powertrain interactions. The enhanced efficiencies in optimized engines, combined with the hybrid control strategy’s role in shifting engine operation toward high-load zones, created a co-optimized design that improved average thermal efficiency by 0.5–6% across cycles. The optimized engines delivered up to 5% fuel savings on their own, with hybridization further amplifying benefits. Co-optimized HPDI engines and hybrid powertrains significantly reduced engine-out emissions by limiting low-load operation, while tank-to-wheel GHG decreased by 28–74% relative to diesel. Well-to-wheel results showed that upstream energy production dominates outcomes, with H2 HPDI reducing tailpipe GHG emissions by 95–98%, but the full benefits depend on the production pathway. These findings underscore the potential of optimized HPDI engines in hybrid trucks to reduce the carbon footprint of freight transportation. The thesis makes an important contribution by providing a structured simulation workflow that informs the optimal engine configuration in a hybrid powertrain design for commercial trucks.