Polymerised whey is widely used in dairy products and can affect digestibility when its high-molecular-weight aggregates and gel structure are modified. This study investigated the digestibility, peptide profiles and satiety of modified whey protein isolate (MWPI) pre-heated with transglutaminase. Results showed that 43.06 % of MWPI was digested during the 4-h in vitro digestion, indicating a slow digestion rate. Compared with whey protein isolate (WPI), MWPI yielded 103 peptides with higher abundance following in vitro digestion, including 17 angiotensin-converting enzyme inhibitors and 1 dipeptidyl peptidase-4 inhibitor. Visual analytics indicated differential peptides located at distinct α-helix and β-sheet of β-lactoglobulin, α-lactalbumin and bovine serum albumin. MWPI gavage extended stomach retention time, decreased intestinal propulsion rate from 75.60 % (WPI group) to 33.72 % in 30 min and enhanced satiety within 120 min compared with WPI. Overall, whey polymerisation modulates protein–enzyme interactions, releasing different peptides and enhancing satiety.