Aiming to achieve the synergistic optimization of impurity removal efficiency for the inclined seed cotton cleaner and the quality of cotton fibers post-cleaning under varying seed cotton moisture regain levels, the design of a device that adjusted the rotation angle of elliptical rods to modify the gap between adjacent grids was presented. It provided a systematic account of the device’s key structure and operating principle, and established the adjustable range of parameters (8.5~12.5mm) through geometric calculations. Drawing on the test results of mass, destructive force, and destructive energy of single seed cotton lumps under a moisture regain range of 5.5%~11.5%, the elastic collision process between single seed cotton lumps and spikes during the cleaning stage was analyzed, and the testing range for the spike roller’s rotational speed was defined as 560~760r/min. Building on the definition of the aforementioned testing parameter ranges, a quadratic regression orthogonal rotational combination experimental design was implemented—with spike roller rotational speed, seed cotton feeding rate, gap between adjacent grids, and seed cotton moisture regained as experimental factors, and the machine’s impurity removal efficiency and seed cotton short fiber rate as evaluation indices. From this design, regression equations describing the relationships between the evaluation indices and individual experimental factors were derived. Furthermore, a mapping relationship between seed cotton moisture regain and processing parameters was established by using the non-dominated sorting genetic algorithm with an elitist strategy (here after referred to as NSGA-Ⅱ). Verification tests under multiple operating conditions demonstrated that in comparison with the pre-optimization state, the machine’s impurity removal efficiency was enhanced by a maximum of 14.14 percentage points, while the seed cotton short fiber rate was decreased by a maximum of 11.22 percentage points. For different parameter combinations, the maximum relative error associated with the machine’s impurity removal efficiency was less than 4.59%, and that for the seed cotton short fiber rate was less than 2.80%, thereby validating the reliability of the regression model and the optimized parameters.