The present work intends to make a scientific contribution to future drive technology in medium-duty road freight transportation that is as objective and fact-based as possible. In cooperation with a medium-sized forwarding company, 1-day transports, previously driven with diesel trucks, were examined. Using a physically based model, which was first validated by comparing simulated CNG drive data with real-world diesel data, the findings were transferred to battery electric trucks (BETs) and fuel cell trucks (FCETs) and extrapolated to 2050 based on expected technological developments. The model makes statements based on the results of the investigated application regarding specific consumption, greenhouse gas (GHG) emissions, consumption shares and recuperation. The CNG combustion technology (ICET-CNG) serves as a reference. BETs in this application have the lowest emission and consumption values: BET2050 will consume a third of the energy and emit a fifth of the GHGs of ICET-CNG2024. The weight of the battery leads to higher consumption values. FCETs have higher fuel consumption due to their longer drive trains. This is partially compensated by their lower weight: FCET2050 will consume 40% of the energy and emit a third of the GHGs of ICET2024. In long-distance traffic, aerodynamic drag is the dominant consumption factor, accounting for 40%, which should be addressed in further truck development. Recuperation extends the range by 3–7%.