Background: Licorice, one of the most commonly used phytomedicines in Asia, has detoxication and anti-oxidation properties. Due to the exhausted wild resources, licorice is obtained mainly from cultivation, and the suitable conditions under cultivation lead to a serious decline in quality. Objectives: To establish a method to improve the quality of cultivated licorice by environmental stress. Materials and Methods: The fresh roots of Glycyrrhiza uralensis were soaked in 5%, 10%, and 20% polyethylene glycol-6000 (PEG) for 4 days to construct a physiological state of drought. The changes in hydrogen peroxide (H2O2) and enzymes related to secondary metabolism in the treated licorice were observed, and their detoxication and anti-oxidation were verified by reducing aconite-induced cardiotoxicity and free radical scavenging rate experiments. Results: The H2O2 content notably boosted, and gene expression and allosterism of enzymes related to secondary metabolism such as 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR), squalene synthase (SQS), β-amyrin synthase (β-AS), and phenylalanine ammonia-lyase (PAL) were promoted, and enhance their activities. Under a drought stress of 10% PEG, secondary metabolites significantly increased, and the effectiveness of the drug also intensified. For the myocardial injury caused by aconite, compared with the untreated, creatine kinase (CK), cardiac troponin-T (cTn-T), and lactate dehydrogenase (LDH) decreased by 9.3%, 14.6%, and 6.3% in the 10% PEG. Meanwhile, the clearance rates of 1,1-diphenyl-2-picryl hydrazyl radical (DPPH·) and hydroxyl radical (OH·) heightened by 7.5% and 13.1%, separately. Conclusion: Drought stress can greatly increase the secondary metabolites of licorice and enhance its detoxication and anti-oxidation.