Inflammatory bowel disease remains a significant challenge in clinical settings. This study investigated the therapeutic potential of sea cucumber ovum hydrolysates (SCH) in a dextran sulfate sodium (DSS)-induced colitis mouse model. SCH, defined by its elevated stability and solubility, with a molecular weight below 1000 Da, significantly alleviated DSS-induced colitis, as evidenced by enhanced splenic index, reduced colonic damage, and diminished serum pro-inflammatory cytokines. Furthermore, macrogenomic analysis demonstrated that SCH increased beneficial gut microbes and decreased pro-inflammatory bacteria. Furthermore, metabolomic analysis of colonic tissues identified elevated levels of anti-inflammatory metabolites, such as Phenyllactate, 2-Hydroxyglutarate, and L-Aspartic acid, in colitis mice after oral administration of SCH. In conclusion, SCH represents a promising candidate for the treatment of colitis.