The conditions for the solid–liquid extraction of the antioxidant polyphenol compounds from yellow passion fruit seeds were optimized by response surface methodology with the following variables as the extraction parameters: extraction time (12.8–147.2 min), ethanol concentration (13–97%), and temperature (16.4–83.6 °C). The polyphenol content and antioxidant capacity, which were assessed by the 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity, oxygen radical absorbance capacity, β-carotene bleaching assay, and ferric reducing antioxidant power assay, were considered dependent variables. The association of the dependent variables was effective for explaining the effect of the independent variables within a determination coefficient (R 2) range of 0.88–0.96. A moderate-to-strong correlation for the polyphenol content and antioxidant capacity by the investigated methods was established, and optimized conditions were employed to maximize this response. Extraction was carried out at 80 °C using 70% ethanol concentration for 30 min, which was the most efficient condition to obtain an extract with high concentrations of polyphenolic compounds (3.12 g gallic acid equivalent/100 g seed dry basis) and a strong antioxidant capacity. The stilbene piceatannol was the major compound identified by liquid chromatography-electrospray ionization-tandem mass spectrometry (3.68 g/100 g seed dry basis). These results reinforce that agro-industrial waste demonstrates potential as a source of bioactive compounds, with implications in human health as well as in food and chemical industries.