Optimal conditions for polyphenols extraction from plants are moderate conditions and being water‐based is mandatory. In this work, a response surface methodology (RSM) was used to attain optimal conditions for polyphenols extraction from yerba mate (YM, South‐America infusion) using water as solvent under ultrasound (US). The following parameters were varied: mass of YM/volume of water (YM/W), pH, temperature, and time. The optimal conditions were 90°C with a YM/W of 150 g L−1 for 5 min, at which the highest total polyphenol content (TPC) concentration (11,300 mg GAE L−1) was found, together with an antioxidant activity of 132 mmol Trolox equivalent (TE) L−1 of extract. The conditions obtained from the RSM method were applied to other methods as follows: extraction without stirring, magnetic stirring assisted extraction and US with magnetic stirring assisted extraction. Results indicated that the US‐assisted extraction was the most efficient for extracting polyphenols under these conditions. This study helps to developing an eco‐friendly and cost‐effective experimental design, reducing the production of wastes, and using a very fast water‐based method.