Abstract Nuclear power is considered as the most promising energy for power generation due to low carbon emission, small fuel cost, high efficiency and reliability. As a new type of heat exchanger, printed circuit heat exchanger (PCHE) with high compactness and efficiency can be used for the supercritical carbon dioxide (SCO2) Brayton power cycle in the Gen IV nuclear reactor systems to transfer great amount of heat from nuclear reactors. The chemical etching technology plays an important role in production of heat transfer channels for PCHEs from micron level to millimeter level. In order to produce high-quality heat transfer channels, the chemical spray etching method is used in the manufacturing process. In this work, a chemical spray etching experiment was carried out to analyse the etching phenomenon on the PCHE channels. The influences of etching parameters, such as etching rate, lateral erosion, surface roughness, etc., are investigated. The results showed that the etching parameters significantly affected the etching quality, which provided comprehensive view of details for the etching process. Besides, an orthogonal array testing strategy (OATS) was adopted for chemical spray etching to synthetically study the influences of FeCl3 and H3PO4 concentrations, etching temperature, spray pressure on the etching rate, the lateral erosion and the surface roughness. The optimal combination of etching parameters in the setting level was investigated and obtained, which is in the condition with spray gage pressure of 0.15 MPa, etching temperature of 35 °C, FeCl3 concentration of 400 g·L−1 and H3PO4 concentration of 1.5 M. The present work is of significance to realize the low-cost, high-efficiency and controllable manufacturing process of PCHEs.