Recent developments in agriculture mechanization have generated significant challenges towards sustainable approaches to reduce the environmental footprint and improve food quality. This paper highlights the benefits of using unmanned aerial systems (UASs) for precision spraying applications of pesticides, reducing the environmental risk and waste caused by spray drift. Several unmanned aerial spraying system (UASS) operation parameters and spray system designs are examined to define adequate configurations for specific treatments. A hexarotor DJI Matrice 600 equipped with T-Motor 15“×5” carbon fiber blades is tested numerically using computational fluid dynamics (CFD) and experimentally in a wind tunnel. These tests assess the aerodynamic interaction between the wake of an advancing multicopter and the fine droplets generated by atomizers traditionally used in agricultural applications. The aim of this research is twofold. First, we analyze the effects of parameters such as flight speed (0, 2, and 3 m.s−1), nozzle type (hollowcone and fan), and injection pressure (2–3 bar) on spray distribution. In the second phase, we use data from the experimental campaign to validate numerical tools for the simulation of rotor–droplet interactions necessary to predict spray’s ground footprint and to plan a precise guidance algorithm to achieve on-target deposition and reduce the well-known droplet drift problem.