In this article, methods for the attitude control optimization of large-load plant-protection quadrotor unmanned aerial vehicles (UAVs) are presented. Large-load plant-protection quadrotors can be defined as quadrotors equipped with sprayers and a tank containing a large amount of water or pesticide, allowing the quadrotors to water plants or spray pesticide during flight. Compared to the control of common small quadrotors, two main points need to be considered in the control of large-load plant-protection quadrotors—first, the water in the tank gradually diminishes during flight and the physical parameters change during this process. Second, the size and mass of the rotors are especially large, which greatly slows the response rate of the rotors. We present an extended-state reinforcement learning (RL) algorithm to solve these problems. The moment of inertia (MOI) of the three axes and the dynamic response constant of the rotors are included in the state list of the quadrotor during the training process, so that the controller can learn these changes in the models. The controlling laws are automatically generated and optimized, which greatly simplifies the tuning process compared to those of traditional control algorithms. The controller in this article is tested on a 10 kg class large-load plant-protection quadrotor, and the flight performance verifies the effectiveness of our work.