Platooning represents a crucial strategy for mitigating emissions from heavy-duty vehicles (HDVs). This study evaluates the effects of platoon composition on the surrounding airflow utilizing a computational fluid dynamics (CFD) model, and quantifies the resultant fuel efficiency and CO2 emissions. This study examines fuel consumption data reconstructed from field experiments to validate the CFD model’s ability to accurately simulate drag forces within a homogeneous three-truck platoon. The potential for fuel savings was assessed based on CFD-simulated fuel consumption, taking into account various inter-vehicle distances and driving speeds. The model successfully reproduced the fuel consumption observed in a platooning formation comprising lead, middle, and trailing trucks, with an error margin below 6.2%. While the lead and middle trucks exhibited increased fuel consumption with greater inter-vehicle distances, the trailing truck showed decreased fuel consumption with specific distance-to-length ratios (D/L), followed by an increase from a D/L of 1.1. Additionally, a significant decrease in total fuel efficiency was noted for D/L ratios exceeding 1.5. Considering the diverse platooning scenarios analyzed, the study anticipates an annual reduction of up to 7 tons of CO2 equivalent per vehicle. By optimizing platooning configurations, this research contributes to enhancing fuel efficiency and reducing emissions from HDVs.