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Drought adaptation of plants is closely related to resistance and tolerance to drought stress as well as the ability to recover after the elimination of the stress. Glycyrrhiza uralensisFisch is a commonly applied herb whose growth and development are greatly affected by drought. Here, we provide the first comprehensive analysis of the transcriptomic, epigenetic, and metabolic responses of G. uralensisto drought stress and rewatering. The hyper-/hypomethylation of genes may lead to up-/downregulated gene expression, and epigenetic changes can be regarded as an important regulatory mechanism of G. uralensisunder drought stress and rewatering. Moreover, integrated transcriptome and metabolome analysis revealed that genes and metabolites involved in pathways of antioxidation, osmoregulation, phenylpropanoid biosynthesis, and flavonoid biosynthesis may regulate the drought adaptation of G. uralensis. This work provides crucial insights into the drought adaptation of G. uralensisand offers epigenetic resources for cultivating G. uralensiswith high drought adaptation.