Background and purpose: Carvacrol, a monoterpenoid phenol derived from Lamiaceae plants, exhibits anti-inflammatory activity but is limited by poor bioactivity and low target specificity. In this study, we aimed to develop a more potent derivative and investigate its anti-inflammatory mechanisms in vitro and in a DSS-induced colitis model. Experimental approach: A novel carvacrol derivative, ZYZ311, was synthesized and subjected to comprehensive pharmacological evaluations. Anti-inflammatory effects were assessed in LPS-stimulated RAW264.7 macrophages and a DSS-induced mouse model of ulcerative colitis. Mechanistic studies, including molecular docking, cellular thermal shift assays, and signaling pathway analyses, were conducted to explore the interaction between ZYZ311 and inflammatory targets. Key results: ZYZ311 exhibited significantly enhanced anti-inflammatory effects compared to carvacrol. In vitro, ZYZ311 markedly reduced nitric oxide and interleukin-6 (IL-6) production, downregulated IL-6, COX-2, and NOS2 expression, and without inhibited tumor necrosis factor-α (TNF-α). Mechanistically, ZYZ311 acted predominantly in the mid-to-late phase of inflammation by directly binding to STAT3 and inhibiting its phosphorylation at Tyr705, thereby suppressing IL-6-mediated JAK2-STAT3 signaling, without significantly affecting early NF-κB activation. In vivo, ZYZ311 alleviated clinical symptoms and histological damage in DSS-induced colitis and reduced STAT3 activation in colonic tissues. Conclusion and implications: ZYZ311 is a novel STAT3-targeted agent that significantly attenuates inflammation in vitro and in vivo, highlighting its potential as a promising therapeutic candidate for chronic inflammatory diseases such as ulcerative colitis.