Abstract: Parameter sensitivity analysis is an important part of model uncertainty analysis, which helps to identify key parameters and improve the efficiency of parameter optimization. Taking water quality simulation of the sewage outlet in the 5 000 m × 200 m test river section as the research object, the perturbation analysis method was used to study the parameter sensitivity of MIKE21 water quality model. The results showed that: ① The parameters affecting MIKE21 water quality model mainly included grid size, roughness parameter, decay coefficient and diffusion coefficient. ② The sensitivity of the four parameters to the overall calculation results of water quality were insensitive, weak sensitive, relatively sensitive and extremely sensitive, and the decay coefficient was the decisive parameter affecting the calculation results of the water quality model. ③ The influence of grid size and diffusion coefficient on the calculation results of water quality model was mainly reflected in the near-area of sewage outlet. The influence of roughness parameter and decay coefficient on the calculation results was global, the further distance apart from the outlet, the more obvious the cumulative effect was. The research has a certain reference value for the parameter optimization in the demonstration of sewage outflet setting and water quality impact simulating based on MIKE21 model.