Flourensia cernua, commonly known as hojasén, is an endemic species from northern Mexico used in herbal medicine as a remedy for various stomach and respiratory ailments. In addition to its medicinal applications, this plant has notable antioxidant potential, making it a promising area of study. A crucial aspect in plant studies is the extraction method used, as conventional approaches can diminish the bioactivities present and affect the environment. This study aims to compare two sustainable extraction techniques, ultrasound and microwave-assisted (UAE/MAE), to maximize the yield of polyphenolic compounds from F. cernua. The Taguchi L18 orthogonal array was employed to evaluate total polyphenols and to examine independent variables, such as solvent concentration, temperature, and time. Additionally, the total flavonoid content and antioxidant activity were evaluated using the radicals ABTS^●+ and DPPH^●, and the compounds were identified using RP-HPLC-ESI-MS. The results indicated that ultrasound showed better performance in recovering total bioactive compounds, correlating with antioxidant activity. Moreover, the in vitro, hemolytic, and antihemolytic assays demonstrated that F. cernua extracts are biocompatible and exhibit significant protective activity against oxidative damage in erythrocytes, supporting their potential cytoprotective and antioxidant properties. This suggests that ultrasound-assisted extraction (UAE) is an effective method for extracting phenolic compounds from F. cernua, with potential for optimizing conditions and facilitating biotechnological and therapeutic applications.