Active peptides, as an alternative nutrition supplement, have been confirmed to have beneficial efficacy against acute colitis. Herein, egg white peptides (EWPs) were used as a nutritional supplement to relieve dextran sulfate sodium-induced acute colitis symptoms. The potential multi-component synergetic pharmacological intervention mechanism of EWPs was investigated on the basis of in silico pharmacology, bioinformatics analysis, and molecular docking. In vitro experiments demonstrated that the migration rate of HSF cells was enhanced 5.30-fold upon treatment with EWPs relative to the control group. After administration with EWPs, colitis symptoms were alleviated in a dose-dependent manner and the serum amino acid content was significantly enhanced, especially for Ala, Leu, Ser, Thr, and Met. Four peptides identified from EWPs showed a total of 52 acute colitis-related potential targets (Fit score >3.8) with network pharmacology analysis, and the targets participated in 31 signaling pathways (p < 0.001). Among these pathways, PI3K-Akt, VEGF, Ras, TNF, and MAPK signaling pathways may exert essential anti-inflammatory effects and accelerate repairing intestinal mucosa. Molecular docking showed that the majority binding energy of peptides-targets was between -10.35 kcal mol-1 and -18.72 kcal mol-1, and peptides mainly interacted with the core targets (Btk, Gstm1, and Rac1) by hydrogen-bonding interactions. The current study confirmed that EWPs as supplementary nutrition can alleviate acute colitis.