Scientific interest has currently focused on natural products as a feasible approach for new food additives to replace synthetic preservatives. Thereby, the objective of this work was to optimize the polyphenol extraction from native Amazonian plant species Dalbergia monetaria L.f. and Croton cajucara Benth., and they were determined by the total content of these compounds. Accordingly, the hydroalcoholic extract’s phytocomposition was analyzed by ultra-high-performance liquid chromatography–diode array detector (UPLC-DAD) and various assays to determine the antioxidant capacity (e.g., 2,2-Diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, ferric reduction power, peroxidation inhibition). In addition, response surface methodology applying a central composite design was used to optimize the antioxidant compound extraction conditions. Extract phytochemical profiles identified polyphenols such as (-)-epigallocatechin gallate, rutin, and hyperoside in both species. Furthermore, D. monetaria and C. cajucara extracts displayed significant antioxidant capacity, exhibiting similar values compared to the standard synthetic antioxidant butylated hydroxytoluene. Nevertheless, C. cajucara showed more antioxidant efficiency compared to D. monetaria. These results were consistent with the distribution matrix obtained by a Central Composite Design since the C. cajucara extracts exhibited the best response to the adopted optimization model. Therefore, data are promising for obtaining potential options for natural additives for the food industry.