Aiming at the popularization and application of a real-time monitoring parameter acquisition system of the electric submersible pump (ESP) well, this paper proposes a fault diagnosis method of ESP well operation based on the SPC rule and prior knowledge fusion. Based on the study of parameter variation rules of ESP well, the SPC expansion rule model is established; by analyzing the variation of some typical characteristic parameters of ESP well, combined with SPC expansion rules and expert experience, a priori knowledge of fault diagnosis of ESP well is formed, that is, multiparameter fault analysis table and weight factor; the SPC extended rule model and prior knowledge are fused to establish the fault probability model of ESP well, form the fault diagnosis method of ESP well, develop the online fault diagnosis software of ESP well, and deploy it in 425 ESP wells in a block. Taking five types of tubing leakage, pump wear, shaft breakage, gas influence, and pump plugging as examples, the application process of fault diagnosis method is analyzed. The research and application show that compared with other fault diagnosis methods, this method needs a smaller time window and higher diagnosis accuracy. By setting multiple time windows, this diagnosis method is applied to calculate the fault probability of ESP well in real time, solve the real time and accurate identification of 14 sudden faults and gradual faults, and significantly improve the intelligent diagnosis level of production faults of ESP well.