Background/Objectives: Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease (IBD) lacking therapies that directly promote mucosal healing, an important clinical endpoint and therapeutic goal for achieving remission and improved long-term outcomes. Epithelial restitution is a key component of effective mucosal healing. EPICERTIN, a novel biotherapeutic candidate, has previously demonstrated epithelial repair activity in dextran sulfate sodium (DSS)-induced colitis models and enhanced epithelial cell viability in human IBD colon explants. To further substantiate its therapeutic efficacy in a UC-relevant context, we evaluated EPICERTIN in acute oxazolone (OXA)-induced colitis in BALB/c mice, a model reflecting the adaptive immune-driven inflammation and histopathologic characteristics of human UC. Methods: Orally administered EPICERTIN, at escalating doses (0.3 µg, 3 µg, and 30 µg), was assessed for therapeutic efficacy in male and female mice through body weight, Disease Activity Index (DAI) scores, and histopathology. Wound healing and immune impacts were examined using qRT-PCR, Imaging Mass Cytometry (IMC), and Cytometry by Time of Flight (CyTOF) in male mice. Results: EPICERTIN effectively mitigated acute OXA-induced colitis. The 3 µg dose provided the greatest benefit, improving body weight recovery and reducing DAI and histopathological damage scores. Treatment reduced Il1b while increasing Cdh1 expression, accompanied by higher levels of epithelial markers (pan-cytokeratin (PanCK), E-cadherin, epithelial cell adhesion marker (EpCAM)) and decreased fibrotic markers (collagen type I, alpha-smooth muscle actin (α-SMA), fibronectin). Moreover, EPICERTIN reduced inflammatory lymphoid and myeloid cells while increasing γδ T cells in the colon lamina propria. Conclusions: Collectively, these results demonstrate that EPICERTIN promotes epithelial restitution, suppresses inflammation, and supports mucosal healing, substantiating its therapeutic potential for UC.