•Phenolics were extracted from MOLs using customised deep eutectic solvents (DES).•DES-based ultrasonic-assisted extraction (UAE) conditions were optimized by RSM.•DES-based UAE exhibited high efficiency for the extraction of the phenolic compounds.•DES-based UAE showed strong antioxidant activities.•Phenolic constituents in the MOLs extracts were analyzed. In this study, an ultrasonic-assisted extraction (UAE) procedure with selected deep eutectic solvents (DES) as solvent was first designed to simultaneously optimize the total phenolic/flavonoid content (TPC/TFC) and antioxidant activities of Moringa oleifera L. leaves (MOLs) by using response surface methodology (RSM). The key factors for RSM were selected based on the design of the experimental results along with a three-factors-five-level, central composite design (CCD), including 20 experimental runs. The analysis of variance (ANOVA) results revealed that the water content in DES had a significant influence on all responses, while the ultrasonic time and the ratio of liquid to solid had no statistically significant effects on the total phenolic content. The optimal conditions of the combination of TPC/TFC and antioxidant activities were obtained as follows: 37% water content in DES, 144 W ultrasonic power, and 40 °C ultrasonic temperature. The measured parameters corresponded with the predicted results. Moreover, a comparative study confirmed that the optimized DES-based UAE yielded further higher TPC, TFC, and antioxidant activities than other extraction methods. The results of HPLC analysis in optimized conditions verified that the MOLs extracts with DES-based UAE included 14 phenolic compounds with high concentrations of vicenin-2 (17.6 mg/g) and orientin (23.6 mg/g). The present study supplied a green and high-efficient method for extracting high levels of anti-oxidative phenolic compounds from MOLs.