Background Ginseng rusty root symptoms (GRS) is one of the primary diseases of ginseng. This disease leads to a severe decline in the quality of ginseng. It has been shown that the occurrence of GRS is associated with soil environmental degradation, which may involve changes in soil microbiology and physicochemical properties. Results In this study, GRS and healthy ginseng (HG) samples were used as experimental materials for comparative analysis of transcriptome and metabolome. Compared with those in HG samples, 949 metabolites and 9451 genes were significantly changed at the metabolic and transcriptional levels in diseased samples. The diseased tissues' metabolic patterns changed, and the accumulation of various organic acids, alkaloids, alcohols and phenols in diseased tissues increased significantly. There were significant differences in the expression of genes involved in plant hormone signal transduction, phenylpropanoid biosynthesis, the peroxidase pathway, and the plant-pathogen interaction pathway. Conclusion The current study involved a comparative metabolome and transcriptome analysis of GRS and HG samples. Based on the findings at the transcriptional and metabolic levels, a mechanism model of the ginseng response to GRS was established. Our results provide new insights into ginseng's response to GRS, which will reveal the potential molecular mechanisms of this disease in ginseng.