To improve the laser cleaning surface quality of rust layers in Q390 steel, a method of determining the optimal cleaning parameters is proposed that is based on response surface methodology and the second-generation non-dominated sorting genetic algorithm (NSGA-II). It involves constructing a mathematical model of the input variables (laser power, cleaning speed, scanning speed, and repetition frequency) and the objective values (surface oxygen content, rust layer removal rate, and surface roughness). The effects of the laser cleaning process parameters on the cleaning surface quality were analyzed in our study, and accordingly, NSGA-II was used to determine the optimal process parameters. The results indicate that the optimal process parameters are as follows: a laser power of 44.99 W, cleaning speed of 174.01 mm/min, scanning speed of 3852.03 mm/s, and repetition frequency of 116 kHz. With these parameters, the surface corrosion is effectively removed, revealing a distinct metal luster and meeting the standard for surface treatment before welding.