Hydrogen mobility embodies a promising solution to address the challenges posed by traditional fossil fuel-based vehicles. The use of hydrogen in small heavy-duty road vehicles based on internal combustion engines (ICEs) may be appealing for two fundamental reasons: Direct electrification seems less promising in heavy-duty transport systems, and fuel cell-based hydrogen vehicle implementation may not proceed at the expected pace due to higher investment costs compared to ICEs. On the other hand, hydrogen combustion is gaining attractiveness and relies on robust and cheap technologies, but it is not the only renewable solution. In this framework, this work presents a methodology to assess the Well-to-Wheel primary energy consumption and CO₂ emissions of small heavy-duty vehicles. The methodology is applied in a real case study, namely a passenger coach traveling on a 100 km mission in non-optimized conditions. Therefore, the suitability of hydrogen is compared with standard diesel and other alternative diesel-type fuels (biodiesel and synthetic diesel types). Hydrogen shows competitivity with standard diesel from the point of view of CO₂ emission reduction (−29%) while it hides a higher primary energy consumption (+40%) based on the current power-to-hydrogen efficiency declared by electrolyzer manufacturers. Nonetheless, HVO brings the highest benefits both from the point of view of primary energy consumption and emission reduction, namely −35% and 464–634 kgCO₂/100km avoided compared to hydrogen. Moreover, the availability of HVO—like other biofuels—does not depend on carbon from CO₂ capture and sequestration systems.