In line with EU decarbonization targets for the heavy-duty transport sector, this study proposes an analytical methodology to assess the impact of diesel performance additives on fuel consumption in Euro 6 heavy-duty vehicles, the prevailing standard in the circulating European road tractor fleet. A fleet of five N3-category road tractors equipped with tanker semi-trailers was monitored over two phases. During the first 10-month baseline phase, the vehicles operated with standard EN 590 diesel (containing 6–7% FAME); in the second phase, they used a commercially available premium diesel containing performance-enhancing additives. Fuel consumption and route data were collected using a GPS-based system interfaced with the engine control unit via the OBD port and integrated with the fleet tracking platform. After applying data filtering to exclude low-quality or non-representative trips, a 1% reduction in fuel consumption was observed with the use of fuel with additives. Route-level analysis revealed higher savings (up to 5.1%) in high-load operating conditions, while most trips showed improvements between −1.6% and −3.4%. Temporal analysis confirmed the general trend across varying vehicle usage patterns. Aggregated fleet-level data proved to be the most robust approach to mitigate statistical variability. To evaluate the potential impact at scale, a European scenario was developed: a 1% reduction in fuel consumption across the 6.75 million heavy-duty vehicles in the EU could yield annual savings of 2 billion liters of diesel and avoid approximately 6 million tons of CO₂ emissions. Even partial adoption could lead to meaningful environmental benefits. Alongside emissions reductions, fuel additives also offer economic value by lowering operating costs, improving engine efficiency, and reducing maintenance needs.