The work aims to analyze the influence of laser cleaning process on the surface quality of Q345C steel rust layer and optimize the laser cleaning process parameters to provide support for laser derusting of Q345C steel pipe pile. The rust layer on the surface of Q345C steel was cleaned by nanosecond pulsed laser. The surface removal rate, surface oxygen content and surface roughness of Q345C steel were measured respectively by Image-Pro-Puls software, field emission scanning electron microscope and confocal microscope. Based on the response surface methodology, the mathematical models between laser cleaning process parameters and cleaning surface quality were established under the combination design method of BOX-Benhnken to analyze the trend of interaction between laser cleaning process parameters on the cleaning surface quality. On this basis, the parameters were optimized and the optimization results were experimentally verified. According to the analysis of response surface, the optimum cleaning parameters for 100 μm thick Q345C steel rust layer were: laser power of 53 W, repetition frequency of 80 kHz and scanning speed of galvanometer of 5555 mm/s. After laser cleaning, the surface quality was prestantious and exposed the color of the metal without residual rust layer, reaching the level of Sa2.5. Under the process parameters, the surface removal rate was 91.37%, the surface oxygen content was 2.41wt%, and the surface roughness was 7.09 μm, which conformed to the requirements of rust removal technology for steel pipe pile. The mathematical model between the laser cleaning process parameters and the cleaning surface quality can be used for Q345C steel surface topography prediction and process parameter optimization. Laser derusting can use the suitable process parameters to achieve good surface quality and high derusting efficiency.