Plant-based foods have long been recognized for their health-promoting properties, particularly in combating oxidative stress-related disorders. Ferocactus pilosus inflorescences have been consumed in Mexico since pre-Hispanic times; however, their nutritional potential remains largely unexplored, with limited research on their polyphenolic composition and antioxidant properties. This study aims to bridge that gap by quantifying the polyphenolic content of F. pilosus inflorescences and assessing their antioxidant activity. Methodology: Inflorescences were collected from Ejido Guadalupe Victoria, Coahuila, Mexico, then cleaned, dehydrated, ground into flour, and sieved for uniformity. Phytochemical extraction was performed using 70% and 35% ethanol with a hybrid microwave–ultrasound reaction system. The extracts underwent partial purification via column chromatography using Amberlite XAD-16 resin, yielding polyphenols in powdered form. Hydrolysable polyphenols (HP) and condensed polyphenols (CP) were quantified, while antioxidant activity was evaluated using DPPH, ABTS, and FRAP assays. The extracts contained moderate levels of HP (4.76 mg/g GAE DW) and CP (6.91mg/g CE DW), demonstrating notable antioxidant potential: DPPH (0.73 mg TE/g), ABTS (0.37 mg TE/g), and FRAP (0.66 mg TE/g). F. pilosus inflorescences represent a valuable source of polyphenols with significant antioxidant capacity, suggesting potential applications in nutraceuticals and functional foods. Further research is warranted to explore their bioavailability and health benefits.