In this study, polyphenols in the crude extract (CE) from red onion peel were recovered by macroporous resin, and their antioxidant and anti-inflammatory activities were evaluated. Among the four resins screened (SP850, XAD2, XAD7HP, and XAD16N), XAD7HP showed the highest desorption and recovery ratios, and it was used to optimize polyphenol recovery through single-factor experiments. The optimal conditions were established as 1 g resin, pH 4, 25 °C, 7 h for adsorption, followed by desorption with 70% ethanol for 1 h at 25 °C. These conditions achieved 85.00% adsorption ratio, 87.10% desorption ratio, and 20.9% yield of the macroporous resin-recovered extract (MRE) from the CE. HPLC analysis revealed that rosmarinic acid, quercetin, and myricetin were major compounds in the MRE, with the content of these compounds higher (about 7-fold) compared to the CE, confirming enhanced recovery of polyphenols by macroporous resin. Moreover, FT-IR and ¹H-NMR analysis confirmed the successful recovery of these polyphenol compounds in the MRE. Furthermore, the MRE displayed significantly improved antioxidant activities (DPPH, ABTS, and FRAP) and anti-inflammatory activities (inhibition of nitric oxide synthesis and reactive oxygen species production) compared to the CE. In summary, our findings suggest that macroporous resin can effectively recover polyphenol compounds from red onion peel extract and enhance their biological activities.