Background: Crop rotation plays an important role in improving soil chemical properties, minimizing the presence of disease pathogens, and assists in neutralizing autotoxic effects associated with allelochemicals. Methods and Results: Five rotation crops of sudan grass, soybean, peanut, sweet potato, and perilla were cultivated for one year with an aim to reduce yield losses caused by repeated cropping of ginseng. In 2-year-old ginseng grown in the same soil as a previous ginseng crop, stem length and leaf area were reduced by 30%, and root weight per plant was reduced by 56%. Crop rotation resulted in a significant decrease in electrical conductivity, NO3, and P2O5 content of the soil, whereas organic matter, Ca, Mg, Fe, Cu, and Zn content remained-unchanged. Soil K content was increased following crop rotation with sudan grass and peanut only. Rotation with all alternate crops increased subsequent ginseng aerial plant biomass, whereas root weight per plant significantly increased following crop rotation with perilla only. A significant positive correlation was observed between root rot ration and soil K content, and a significant negative correlation was observed between ginseng root yield and the abundance of actinomycetes. Crop rotation affected the soil microbial community by increasing gram negative microbes, the ratio of aerobic microbes, and total microbial biomass whereas decreases were observed in actinomycetes and the ration of saturated fatty acids. Conclusions: In soil exhibiting crop failure following replanting, crop rotation for one year promoted both soil microbial activity and subsequent ginseng aerial plant biomass, but did not ameliorate the occurrence of root rot disease.