<p>Generally, conventional manual sprayers are used to apply agrochemicals for controlling disease and pests in sugarcane crops, but often results in inadequate control because of high crop height. Also, tractor-operated sprayers cause plant damage, which is often avoided due to crop physiological parameters. They have low spray efficiency and produce a lot of chemical waste. In these scenarios, an unmanned aerial vehicle (UAV)-based spraying system has significant potential to apply agrochemicals effectively and precisely to sugarcane crops. However, operating parameters of such sprayers significantly affect spray performance and pest control. Therefore, this study optimized the operational parameters of UAV-based spraying system in sugarcane crops. Response surface methodology (RSM) along with the central composite design was used to study the effect of independent variables of flight height (1.5, 2, and 2.5 m above crop canopy) and flying speed (3, 4, and 5&#xa0;m/s) on response variables. The response variables, i.e., droplet density, droplet size, coverage, spray deposition, uniformity coefficient, and relative span factor values on top, middle, and bottom canopy of sugarcane plant were 96.38, 91.57, 86.93 droplets/cm², 131.29, 129.37, 126.82 µm, 12.05, 11.14, 10.34%, 0.583, 0.548, 0.512 µL/cm², 1.81, 1.76, 1.72 and 1.01, 0.98, 0.96, respectively, at optimized parameters of flight height 1.5 m and flying speed 3&#xa0;m/s, respectively. The spray deposition was nearly negligible in off-target zone at optimized parameters. The field capacity, field efficiency, and application rate of UAV were 2.53 ha/h, 58.56%, and 40.79 L/ha for these optimized parameters. The present study provides recommendations to manufacturers, farmers, and UAV operators for more effective and efficient spraying in sugarcane crops at a height of 1.5 m above the crop canopy and a flying speed of 3&#xa0;m/s.</p>