Replant diseases (RDs), intraspecificnegativeplant–soilfeedback, often stem from nutrient deficiency, allelopathy, or pathogen accumulation. However, the RDs of certain crops are long-lasting and their causes remain unknown. We examined Panax quinquefolius RD in a space-for-time soil sequence representing crop rotation restoration over 1, 10, and 20 years using multiomics and bioassays. Compared with the soils with no ginseng cultivation history, we found 110 significant potential factors related to RD, surprisingly, 53 of which remained unrestored after 20 years. Soil pH and the levels of organic nutrients (amino acids, carbohydrates, and alditols), allelopathic-promoting metabolites (phenolic acids, amines, pyridines, etc.), and beneficial bacteria (Sphingomonas, Burkholderia-Caballeronia-Paraburkholderia, and Terrabacter) and fungi (Acremonium, Penicillium, and Naganishia) decreased, while the levels of allelochemicals (pyruvic and fatty acids) increased. The expression of all metabolic pathways was significantly down-regulated, with the exception of the up-regulated fatty acid-related metabolic pathways. We confirmed that decreased organic nutrient levels and increased levels of allelochemicals impaired P. quinquefolius growth. Soil metabolic factors rather than microbial factors were dominant by network analysis. In conclusion, we found that the overall changes in nutrient levels and metabolic and microbial factors contributed to short-term RD (1–10 year) persistence, whereas long-term RD (after 20 years) primarily resulted from disordered soil metabolite levels and pathways. This research will help deepen our understanding of the relationship between RD and potential changes in the factors influencing RD that are caused by soil legacy effects of valuable plants and provide theoretical guidance for effective soil quality improvement.