Conventional whey protein concentrate (WPC) and gently processed skim-milk-derived WPC (SPC) undergo heat processing to ensure microbial safety before use in infant formula products. Heat treatment and storage induce protein structural changes, which may modulate digestibility and bioactivity. The objective of the study was to evaluate the effect of heat treatment and storage on the SPC ingredient by subjecting it to heat treatment (80 °C, 30 s) with or without an additional six-week storage at 37 °C (resulting in HT-SPC and HTS-SPC, respectively) and to compare these effects with a reference WPC ingredient. Reducible aggregates were present in HT-SPC, HTS-SPC, and WPC but not in the control SPC ingredient. As assessed in vitro, infant gastric digestion conditions had a limited hydrolytic effect on whey proteins, while significant protein hydrolysis occurred under infant intestinal conditions. WPC was more digestible than SPC, and additional heat treatment of SPC increased the protein digestibility. The digested protein ingredients exhibited similar anti-inflammatory activity (e.g., inhibition of the NFκB pathway in THP-1 macrophages in vitro). In conclusion, the SPC ingredient was less digestible, which was improved by heat treatment but with similar bioactivity as a conventional WPC ingredient.