A progressive optimization iterative strategy was adopted to systematically optimize the nine-steaming and nine-drying process of Polygonatum. The dynamic changes in sensory quality, content of active substances and immunomodulatory activity of polysaccharides during the processing were clarified, and the scientific connotation of the nine-steaming and nine-drying technique was revealed. The results showed that the four-steaming and four-drying Polygonatum yielded the highest score, and further processing led to a decline in flavor and texture. With the increase in processing times, the content of ethanol-soluble extractives decreased gradually from 85.91% in the raw sample to 63.50% in the nine-steaming and nine-drying product, while the polysaccharide content decreased from 9.86% to about 3%. However, the maximum contents of total saponins, flavonoids and total phenols increased by 5.2-, 14.4- and 100 times, respectively. Animal experiments showed that the crude polysaccharides of Polygonatum at each processing stage could improve the immune function of immunosuppressed model mice, and the effects of most Polygonatum groups were better than those of the positive drug. Among them, the four-steaming and four-drying group had the strongest regulatory effect on immunosuppressed mice, and could more effectively repair the micropathological structure of the spleen and thymus. Its organ indices, serum cytokines (IL-2, IFN-γ) and immunoglobulin (IgA, IgM) levels were significantly better than the raw and nine-steaming and nine-drying groups. This study revealed the processing mechanism of the nine-steaming and nine-drying technique of Polygonatum from multiple dimensions of sensory quality, active components and immunomodulatory activity of polysaccharides, clarified the optimal processing node, and provided a scientific basis for the standardization of the processing technique, quality improvement and rational application of Polygonatum.