Polygonum multiflorum Thunb. (Heshouwu in Chinese, PMT) is commonly used as a food supplement due to its anti-aging effects. Maximizing the recovery of active compounds and removing hepatotoxic compounds from PMT are effective ways to reduce side effects. In this study, 71 deep eutectic solvents (DESs) were prepared to simultaneously extract active compounds and remove hepatotoxic compounds from PMT by ultrasound-assisted extraction. Betaine-sorbitol (Bet-Sor, 1:1.2 mol/mol) was screened as the most appropriate DES in this series. Afterwards, the major extraction parameters were optimized using single-factor tests and response surface methodology. The optimal conditions (water content of DES of 46.22 %, liquid/solid ratio of 42.50, and extraction time for 20.76 min) resulted in the maximum total contents of active compounds (25.612 mg/g). Compared with conventional extraction solvents, the highest/lowest extraction amounts of active/hepatotoxic compounds were obtained. At the meantime, Bet-Sor exhibited the highest anti-oxidative effects and the lowest hepatotoxicity on HepG2 cells. The scanning electron microscopy test revealed that the cell walls of PMT cells were extremely injured by Bet-Sor, thus the active components could be fully extracted. These results revealed that DES-based extraction provided a simple, ecofriendly and feasible detoxication strategy to ensure the effective and safe utilization of PMT.