Abstract Aqueous ultrasound-assisted extraction (UAE) of grape pomace was investigated by Response Surface Methodology (RSM) to evaluate the effect of acoustic frequency (40, 80, 120kHz), ultrasonic power density (50, 100, 150W/L) and extraction time (5, 15, 25min) on total phenolics, total flavonols and antioxidant capacity. All the process variables showed a significant effect on the aqueous UAE of grape pomace (p<0.05). The Box–Behnken Design (BBD) generated satisfactory mathematical models which accurately explain the behavior of the system; allowing to predict both the extraction yield of phenolic and flavonol compounds, and also the antioxidant capacity of the grape pomace extracts. The optimal UAE conditions for all response factors were a frequency of 40kHz, a power density of 150W/L and 25min of extraction time. Under these conditions, the aqueous UAE would achieve a maximum of 32.31mg GA/100g fw for total phenolics and 2.04mg quercetin/100g fw for total flavonols. Regarding the antioxidant capacity, the maximum predicted values were 53.47 and 43.66mg Trolox/100g fw for CUPRAC and FRAP assays, respectively. When comparing with organic UAE, in the present research, from 12% to 38% of total phenolic bibliographic values were obtained, but using only water as the extraction solvent, and applying lower temperatures and shorter extraction times. To the best of the authors’ knowledge, no studies specifically addressing the optimization of both acoustic frequency and power density during aqueous-UAE of plant materials have been previously published.