Waltheria ovata is a medicinal plant belonging to the Sterculiaceae genus. Natural products of Waltheria ovata could be used in the food industry as natural antioxidants due to its high content of polyphenols according to the literature. The main objective in this research was to optimize the extraction of phenolic compounds and the antioxidant activity from Waltheria ovata roots using response surface methodology (RSM). The total phenolic content in different extracts was determined by spectrophotometric method (Folin-Ciocalteu reagent) and the antioxidant activity by using DPPH assay. To optimize the conditions for total phenolic content and antioxidant activity were used three independent variables: solvent/sample ratio (1:10, 1:20 and 1:30 g/mL), temperature (40, 50, and 60°C) and time (40, 50 and 60 mins). The results showed that total phenolic content and antioxidant activity in the experiments ranged from 8.7 to 12.1 mg GAE/g and 76.1% to 96.7%, respectively. The coefficients of determination (R2 values) for phenolic content and antioxidant activity were 0.86 and 0.91, respectively. Under the optimum conditions of 1:20 g/mL, 60°C and 55 mins of extraction, the values for total phenolic content and antioxidant activity were 0.448±0.02 mg GAE/g and 87.00±2.0%, respectively. These data showed that the experimental responses were reasonably close to the predicted responses (0.444 mg GAE/g and 84.67%). Therefore, the results showed that Waltheria ovata can be used as antioxidant in foods.