Peanut skin, a byproduct of peanut processing, contains biologically active phenolic compounds. Herein, we evaluated the bioactivity of digested peanut skin extracts using several parameters. Samples were called aquous extract, phase 1 and phase 2. In phase 1, powdered peanut skin was submitted to simulated oral-gastroduodenal digestion using α-amylase, pepsin, pancreatin, lipase, and bile salts. In phase 2, the digested extract from phase 1 was submitted to simulated colonic digestion using a mixture of carbohydrate-hydrolyzing enzymes. Total phenolic content was determined using the Folin–Ciocalteu method. Phenolic compounds were identified using high-performance liquid chromatography. Antioxidant activity was evaluated using different assays. Enzymatic inhibition was determined for pancreatic lipase and α-glucosidase. Finally, viability of HCT116 cells was monitored. The extracts contained caffeic, coumaric, quinic, protocatechuic, ferulic, ellagic, and gallic acids; quercetin; catechin; epicatechin; B-type procyanidins; and caffeine. Phase 1 (16.1 mg GAE/g of sample) and phase 2 (6.6 mg GAE/g of sample) extracts had lower total phenolic content than the aqueous extract (68.5 mg GAE/g of sample), while the phenolic profile remained similar among the three samples. Phase 1 extract had greater antioxidant activity than phase 2 extract, as evidenced by ORAC (128.97 vs 53.50 µM TE/ g of sample), DPPH (IC50 values of 54.5 vs 176.0 mol TE/g of sample, and FRAP (7.02 vs 2.13 mg GAE/g of sample) values. The half-maximal inhibitory concentrations (IC50) of phase 1 and 2 extracts for pancreatic lipase were 11 and 135 µg of sample/mL, respectively; for α-glucosidase, they were 7 and 33 µg of sample/mL, respectively. The IC50 of cellular viability were 9.4 and 15.9 mg of sample/mL for phase 1 and 2 extracts, respectively. Simulated digestion of phenolic compounds from peanut skin resulted in extracts with important biological activity and without cell toxicity. This common byproduct has potential applications in human health.