Using a global optimization evolutionary algorithm (EA), propagating aleatory and epistemic uncertainty within the optimization loop, and using computational fluid dynamics (CFD), this study determines a design for a 3D tractor-trailer base (back-end) drag reduction device that reduces the wind-averaged drag coefficient by 41% at 57 mph (92 km/h). Because it is optimized under uncertainty, this design is relatively insensitive to uncertain wind speed and direction and uncertain deflection angles due to mounting accuracy and static aeroelastic loading. The model includes five design variables with generous constraints, and this study additionally includes the uncertain effects on drag prediction due to truck speed and elevation, steady Reynolds-averaged Navier–Stokes (RANS) approximation, and numerical approximation. This study uses the Design Analysis Kit for Optimization and Terascale Applications (DAKOTA) optimization and uncertainty quantification (UQ) framework to interface the RANS flow solver, grid generator, and optimization algorithm. The computational model is a simplified full-scale tractor-trailer with flow at highway speed. For the optimized design, the estimate of total predictive uncertainty is +15/−42%; 8–10% of this uncertainty comes from model form (computation versus experiment); 3–7% from model input (wind speed and direction, flap angle, and truck speed); and +0.0/−28.5% from numerical approximation (due to the relatively coarse, 6 × 106 cell grid). Relative comparison of designs to the no-flaps baseline should have considerably less uncertainty because numerical error and input variation are nearly eliminated and model form differences are reduced. The total predictive uncertainty is also presented in the form of a probability box, which may be used to decide how to improve the model and reduce uncertainty.