In this study, a crude polyphenol extract (CPE) from defatted grape seeds was evaluated for antioxidant and cytoprotective effects in PC12 cells. The CPE was then fractionated into a catechin and oligomeric procyanidin fraction (F(cat+olig)) and a polymeric procyanidin fraction (F(pol)), and the bioactivities of the fractions were evaluated individually. F(pol) was the richest in total polyphenol, total flavonoid, and polymeric procyanidin but contained less flavan-3-ol than F(cat+olig). Consistent with these results, F(pol) had the highest 2,2-diphenyl-β-picrylhydrazyl radical scavenging activity and reducing power. Both F(cat+olig) and F(pol) had higher 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic) acid radical scavenging activity than CPE. The resistance of PC12 cells against oxidative stress, after pretreatment with F(pol) (200 μg/mL) for 9 h, was 100.7±2.9% of that in the control. Moreover, pretreating these cells with F(cat+olig) and F(pol) significantly decreased reactive oxygen species generation. These results provide information on a potential new source of antioxidants in the form of a functional food derived from an agricultural by-product.