Technical Abstract: Drift of aerially applied crop protection and production materials was studied using a novel simulation-based Design of Experiments (DOE) approach. Many factors that can potentially contribute to downwind deposition from aerial spray application were considered. This new approach can provide valuable information about the significant level of the impact from all factors that affect drift using simulation software such as AGDISP. The application efficiency, the total downwind drift, the cumulative downwind deposition between 30.48 m (100 ft) and 45.72 m (150 ft), and the deposition at 30.48 m (100 ft), 76.2 m (250 ft), and 152.4 m (500 ft) were established as the performance metrics. The most significant factors were identified using statistical analysis based on simulation results, and suggestions for improvement were made. Through preliminary study, the new simulation-based method has shown the potential for statistic analysis without conducting time-consuming field experiments. The new method can be used to search for the optimal spray conditions, which could be used to generate guidelines for applicators to achieve an optimal spray result. The effective use of simulation tool through the identification of significant factors can greatly simplify the field study.