In order to solve the problem of the uneven distribution of the flow and ammonia concentration field in the selective catalytic reduction (SCR) denitrification system of a 660 MW coal−fired power plant, a three−dimensional computational fluid dynamics (CFD) model was established at a scale of 1:1. The existing flow guide and ammonia fume mixing device were then calibrated and optimized. The relative standard deviation of the velocity field distribution upstream of the ammonia injection grid (AIG) was optimized from 15.4% to 9.9%, with a reasonable radius of the deflector at the inlet flue elbows, and the relative standard deviation of the velocity field distribution above the inlet surface of the first catalyst layer in the reactor was optimized from 25.4% to 10.2% by adjusting the angle between the deflector and the wall plate of the inlet hood. Additionally, with the use of a double−layer spoiler ammonia fume mixing device, the relative standard deviation of the ammonia mass concentration distribution above the inlet surface of the first catalyst layer in the reactor was optimized from 12.9% to 5.3%. This paper can provide a valuable reference with practical implications for subsequent research.