Inflammatory bowel disease (IBD) presents complex pathologies and remains challenging to treat, highlighting the urgent need for innovative therapeutics. This study evaluates KB-0118, a novel BET bromodomain inhibitor targeting BRD4, for its immunomodulatory effects in IBD. KB-0118 effectively inhibited pro-inflammatory cytokines, including TNF, IL-1β, and IL-23a, and selectively suppressed Th17 cell differentiation, a critical driver of IBD pathology. In both DSS-induced and T cell-mediated colitis models, KB-0118 significantly reduced disease severity, preserved colon structure, and lowered IL-17 expression. Mechanistic studies suggest KB-0118’s modulation of Th17-driven inflammation occurs through epigenetic suppression of BRD4, confirmed by transcriptomic analysis showing downregulation of STAT3 and BRD4 target genes. Compared to standard BET inhibitors like JQ1 and MS402, KB-0118 exhibited enhanced efficacy in restoring immune balance in IBD, positioning it as a promising therapeutic candidate for chronic inflammatory diseases. Further investigation into KB-0118’s specificity and long-term effects will be essential to clarify its full clinical potential.