With the development of precision agriculture (PA), low-altitude and low-volume spraying based on unmanned aerial vehicles (UAVs) is playing an increasingly important role in the control of crop diseases, pests, and weeds. However, the aerial spraying quality and droplet drift are affected by many factors, some of which are controllable (e.g., flight and spraying parameters) and some of which are not (e.g., environmental parameters). In order to study the influence of spraying parameters on the UAV-based spraying performance, we propose a UAV-compatible spraying system and a customized experimental platform in this work. Through single-factor test and Box–Behnken response surface methods, four influencing factors, namely spraying height, flow rate, distance between nozzles, and pulse width modulation (PWM) duty cycle, were studied under indoor conditions. Variance analysis and multiple quadratic regression fitting were performed on the test data by using Design-Expert 8.0.5B software, and quadratic polynomial regression models of effective spraying width, droplet coverage density, coefficient of variation, and droplet coverage rate were established. Based on the Z-score standardization, a mathematical model of the comprehensive score with four factors was established to evaluate the spraying quality and predict optimal spraying parameters. Test results indicate that the effect intensity of four influencing factors from strong to weak is PWM duty cycle, flow rate, distance between nozzles, and spraying height, and their optimal values are 98.65%, 1.74 L/min, 1.0 m, and 1.60 m, respectively. Additionally, verification experimental results demonstrate that the deviation between the predicted comprehensive score and the actual value was less than 6%. This paper can provide a reference for the design and optimization of UAV spraying systems.