The use of natural compounds in food development is gaining popularity in response to consumers' growing concerns about their diet. In this context, the application of extracts rich in functional compounds presents an attractive option for industries, with propolis standing out as an ingredient of great potential. The objective of this research was to determine the optimal extraction conditions and evaluate their influence on the polyphenol profile of propolis extracts rich in functional compounds. A Box–Behnken response surface design was employed, considering three factors, time (10-40 min), temperature (30-70°C), and ethanol concentration (40-90%), and two responses: antioxidant capacity (AC) and total polyphenolic compounds (TPCs). Design Expert 11 software was used to model the responses, and principal component analysis (PCA) was conducted to assess the impact on polyphenol profiles. The design generated 15 extraction conditions analyzed in duplicate, with AC results ranging from 5.25 to 0.48 mmol Trolox/100 ml and TPC results ranging from 560.6 to 33.9 mg Gallic acid/100 ml. The results fit quadratic models with R² values greater than 0.9621, showing that ethanol concentration and temperature significantly influenced the extraction process. The optimal conditions for maximizing a functional extract were found to be 31°C, 39 minutes, and 87% ethanol. The polyphenol profile was determined by HPLC, identifying eight compounds (Chrysin, Kaempferol, Quercetin, Sinapic, Ferulic, Caffeic, Cinnamic, and Gallic acids). PCA revealed that temperature negatively affects polyphenol concentration, possibly by facilitating their degradation. Gallic acid concentration increased with prolonged extraction times, while the others increased with higher ethanol percentages. In conclusion, the design allowed the identification of optimal conditions for obtaining a propolis extract rich in functional compounds. It was observed that the functional activity of the extracts is associated with higher amounts of Chrysin, Kaempferol, and Quercetin, which are mainly influenced by increased ethanol concentration and lower temperatures.