Ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE) of bioactive compounds, peels from Opuntia engelmannii cultivar (cv.) Valencia were optimized by response surface methodology. Randomized extraction runs were performed for each of the technologies employed in order to build effective models with maximum (bioactive molecules content and yield) and minimum (antioxidant activity) responses. A 5-level, 4-factor central composite design was used to obtain target responses as a function of extraction time (t), solid to liquid ratio (S/L), methanol concentration (metOH), and temperature (T). Specific response optimization for each technology was analyzed, discussed, and general optimization from all the responses together was also gather. The optimum values for each factor were: t = 2.5 and 1.4 min, S/L = 5 and 5 g/L, metOH = 34.6 and 0% of methanol and T = 30 and 36.6 °C, achieving maximum responses of 201.6 and 132.9 mg of betalains/g, 13.9 and 8.0 mg of phenolic acids/g, 2.4 and 1.5 mg of flavonoids/g, 71.8% and 79.1% of extractable solid and IC50 values for the antioxidant activity of 2.9 and 3.6, for UAE and MAE, respectively. The present study suggested UAE as the best extraction system, in order to maximize recovery of bioactive compounds with a high antioxidant activity.