Whey protein hydrolysate (WPH) is frequently used as a milk-based component in infant formula milk powder due to its enhanced absorption properties. However, specific functional advantages of WPH have not been documented. To create WPH that offers both anti-inflammatory and antioxidant properties, this research combined computer-aided virtual enzymolysis with fragmentomics and molecular docking methods. The best protease combination was identified through a multi-index evaluation system, and in vitro experiments were conducted to confirm the results. Initially, composite enzyme combinations were evaluated via virtual enzymolysis. Based on the composition of polypeptides and amino acids in whey protein single enzymolysis fragments (WPSF) and their potential activity frequency, five individual proteases-chymotrypsin A, proteinase K, papain, ficin, and stem bromelain-were selected for further analysis. Subsequently, the chymotrypsin A + papain (AP) and proteinase K + papain (KP) combinations were chosen based on the proportion, potential activity frequency, and activity scores of peptides in whey protein complex enzymolysis fragments (WPCF). The integration of fragmentomics and molecular docking techniques was employed to refine the composite enzyme combinations. Compared with the WPCF of the AP group (APWPCF), fragmentomics analysis indicated that WPCF of the KP group (KPWPCF) exhibited a significantly greater proportion of dipeptides (60.65 % compared to 49.35 %) and hydrophobic amino acids (32 % versus 19.6 %). Furthermore, the increased ratio of absolute net charge exceeding 0 (61.36 % versus 56.31 %) suggests an enhanced capacity for free radical scavenging, as well as improved potential for digestion and absorption without associated toxicity. Molecular docking techniques revealed that KPWPCF can demonstrate anti-inflammatory and antioxidant properties by interacting with important proteins (P65, IKK-β, iNOS, Keap1) in the NF-κB and Keap1-Nrf2 signaling pathways. Additionally, in vitro studies showed that the whey protein hydrolysate from KP (K-PWPH) has a a higher degree of hydrolysis (DH) (24.76 %), NO inhibition rate (14.85 %), and oxygen radical absorption capacity (9.97 ± 0.41 mmol Trolox/g), with a molecular weight less than 3 kDa. Thus, the combination of proteinase K and papain (KP)-especially the stepwise enzymolysis process that first uses proteinase K followed by papain-can be employed to create whey protein hydrolysates with both anti-inflammatory and antioxidant effects. This research lays a theoretical groundwork for developing functional infant formula milk powder and provides new perspectives for the targeted identification of proteases that produce functional peptides.