The objective of this study was to understand the possible interactions between whey protein and cranberry juice after processing that could impact either the protein digestibility or the bioaccessibility of cranberry antioxidants using an in vitro gastrointestinal digestion model. Whey protein isolate (27 or 54 mg of protein per mL) was dissolved in either cranberry juice or water and used as a model beverage system. Beverages were either non-processed or underwent thermal (low: 85 °C for 1 min, medium: 99 °C for 10 s and long: 99 °C for 5 min) or high-pressure processing (600 MPa for 4 min). After processing, beverages underwent oral (30 s), gastric (2 h) and small intestinal (2 h) digestion. During in vitro digestion, protein hydrolysis was monitored by the o-phthalaldehyde (OPA) assay, SDS-PAGE, soluble amino acid content, and pepidomic profiling using Orbitrap mass-spectrometry. Antioxidant capacity was measured with Ferric Reducing Antioxidant Power (FRAP) and 2,2-azinobis (3-ethlybenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assays before and during in vitro digestion. Whey protein isolate dissolved in water had a significantly higher (p < 0.05) degree of hydrolysis and soluble amino acid content during small intestinal digestion compared to protein dissolved in cranberry juice, suggesting that cranberry juice had an effect on how protein was hydrolyzed during digestion. In all processing treatments except for long thermal processing, water and cranberry juice protein solutions had similar β-lactoglobulin digestibility (p > 0.05), suggesting that the cranberry juice interactions with the protein do not significantly decrease β-lactoglobulin resistance to hydrolysis by pepsin. Peptide formation also differed between whey protein dissolved in either water or juice. Cranberry juice protein solutions showed a slightly lower peptide count compared with whey protein isolate dissolved in water. Antioxidant bioaccessibility by FRAP during gastric digestion significantly increased in cranberry juice with addition of whey protein isolate. This trend might indicate a protective effect of whey protein isolate to cranberry antioxidant compounds.