Cranberry polyphenols (CPs) were obtained via ultrasound-assisted extraction and purification on a macroporous resin X-5 column. A green synthesis method of selenium nanoparticles (SeNPs) using CPs as reducing agents was then developed. Two types of SeNPs (CP-SeNPs1 and CP-SeNPs2) were successfully constructed and characterized. The spherical particles were well-dispersed on the polyphenol templates and the addition of the polyphenols reduced the aggregation of the nanoparticles. Both CP-SeNPs1 and CP-SeNPs2, with average particle sizes of 85.62 +/- 0.11 nm and 107.97 +/- 0.12 nm, respectively, demonstrated radical-scavenging activities and protective effects on erythrocyte hemolysis. CP-SeNPs2 possessed more significant antioxidant activity, as evidenced by its higher radical-scavenging rate and greater enhancement of the erythrocyte antioxidant state compared to those of CP-SeNPs1. This study provides a new application of CPs and confirms their great potential in stabilizing SeNPs.