In this study, the aerodynamic characteristics of wheel layouts in commercial vehicles, including dual and tandem axle wheels, were investigated using Computational Fluid Dynamics (CFD) with isolated and in-vehicle systems. For the dual wheel system, an increase in offset distance reduced the drag by up to 31.2% for the Fackrell A2 wheels thanks to the decrease in the low pressure area behind the wheels. In the case of tandem wheel configuration, drag increased as the axle spread increased. As the axle spread increases, the rear wheels move out of the slipstream of the front wheel, causing a sharp increase in drag, while the front wheels' drag remains constant across all axle spreads. In a realistic commercial vehicle model, the same trend was observed. An increase in offset distance reduced the drag by approximately 4.30%, and the increase in axle spread increased the drag by 4.62%. These results are expected to contribute to the improvement of fuel efficiency and the reduction of greenhouse gas emissions by reducing the aerodynamic drag of commercial vehicles.