This work investigated the effect of the solvent composition and solid/solvent ratio on the extraction of antioxidants from Moringa oleifera Lam leaves using experimental design and compared the efficiency between the ultrasound- (UAE) and ultra-homogenizer (HAE)-assisted extractions. The phytochemical composition of the optimized extracts was investigated by ultra-high-performance liquid chromatography coupled with a high-resolution mass spectrometer (UHPLC-QTOF-MS/MS). The experimental results adequately fitted to quadratic models as indicated by the coefficient of determination (0.71–0.97), low standard errors of estimate, and lack of fit >0.05. The optimum conditions of extraction for both methods were identified as 4:200 solid:solvent (m/v) and a 1:1 water:ethanol (v/v) ratio. Thirty compounds were identified by UHPLC-QTOF-MS/MS, among which quercetin, rutin, kaempferol, alkaloids, and lignins. Both techniques studied were efficient in extracting antioxidants from Moringa leaves. The HAE equipment has a longer extraction time but is more accessible than the UAE equipment. Novelty Impact Statement UAE and HAE parameters were optimized for the recovery of antioxidants from Moringa leaves. HAE and UAE allowed obtaining extracts rich in antioxidant compounds. Impacts of solvent composition and solid/solvent ratio were assessed using RSM, and the optimal conditions found were: 4g of sample for 200 ml of solvent with 1:1 water:ethanol ratio. Quercetin, rutin, kaempferol, alkaloids, and lignins were detected in Moringa extracts using UHPLC-QTOF-MS/MS.