This study evaluates the effect of ultrasound-assisted extraction on the extractability of polyphenols from peanut skins (PS) and their antioxidant, and anticancer activities. The extraction was performed with solid/solvent ratios of 1:20 and 1:30 (w/v) at ultrasound intensity ranging from 5.8 to 15.4 W/cm2 for different extraction times (10, 20, 30 and 40 min). The highest polyphenol yield was 167.46 mg GAE/g dried PS. The most abundant polyphenols were catechin, syringic acid, and vanillic acid. The PS ultrasound extract (PSUE) increased the oxidative stability of sunflower oil by four times its initial level. PSUE possessed high inhibitory activity against MCF-7, HepG-2, HCT-116, and PC-3 cancer cell lines, with IC50 ranging from 1.85 ± 0.13 to 6.1 ± 0.43 μg/ml. In addition, the cytotoxicity of PSUE was examined on HFB4 human normal melanocytes using the MTT assay. These results suggest that PSUE can be used as a natural antioxidant and anticancer agent.