The nuclear instrumentation system (NIS) is a key measurement system for nuclear power plants, which is commonly used for nuclear power and axial power deviation (ΔI) monitor. The main principle of measurement is the positive correlation (approximate linear relationship) between core core power and ex-core detector response. However, during the operation of the nuclear power plant, the change of power distribution under different conditions will lead to a change in the neutron flux leaked to the NIS detector, which in turn will lead to a change in the detector current. The approximate linear relationship between the nuclear power and the response of the ex-core detector will deviate to a certain extent, that is, the uncertainty of the indication signal will be introduced due to the change of power distribution. Therefore, in order to study the uncertainty of the change of core power distribution on the NIS indication signal, this paper takes a typical pressurized water reactor as an example, establishes a theoretical analysis model of the PWR core and NIS indication signal, and studies the influence of power distribution on NIS current and the influence on the indication signal under different conditions. The uncertainty of the NIS indication signal of a typical PWR is quantified by the research results, and the quantification results are verified based on the measured operating data. The results show that the proposed method is feasible, which can be used to quantify the uncertainty of the NIS indication signal under the heap design without measured data, and can provide a reference for the formulation of NIS protection signals.