An optimizing method of operating routes based on the smallest spraying unit is proposed for assisting spraying operations in agricultural plant protection areas, with plant protection unmanned helicopters taken as the study object. The pros and cons of various full-coverage operation methods are analyzed in terms of the selection of return points, the number of swerves and the operating distance, which helps select the optimal operating approach of unmanned helicopters. The smallest spraying unit during plant protection operation is determined according to such parameters as the volumes of unmanned helicopter’s power, fuel and pesticide. The rectangular farmland is subjected to segmentation optimization in light of the rectangular cutting idea for the global planning of the plant protection operation area. The simulation results indicate that this optimizing method can effectively improve the spraying efficiency of unmanned helicopters, reduce the economic loss caused by useless flights and optimize energy consumption and time, which provides a reference solution for future high-standard farmland construction.