G-protein-coupled receptors (GPCRs) play a pivotal role in mediating responses to various hormones, neurotransmitters, and external stimuli, making them essential therapeutic targets for multiple conditions. GPR39, an orphan GPCR that detects changes in extracellular Zn(2+) levels, is widely expressed in diverse tissues such as the pancreas, gastrointestinal tract, liver, kidneys, skin, adipose tissue, and brain. Recent studies have increasingly highlighted the involvement of GPR39 in the pathogenesis and progression of inflammatory diseases. By activating Galphaq, Galphas, and Galpha12/13 signaling pathways, GPR39 modulates key inflammatory signaling cascades, including NF-kappaB and MAPK, thereby inhibiting the release of inflammatory mediators, mitigating tissue damage, promoting cell proliferation, and enhancing tissue repair. Emerging evidence suggests that GPR39 acts as a significant modulator in neuroinflammation, pancreatitis, inflammatory bowel disease, arthritis, and skin wound healing Moreover, investigations into exogenous agonists like TC-G 1008 have further substantiated the therapeutic potential of GPR39 in inflammatory diseases. This review elucidates the molecular mechanisms of GPR39 and its multifaceted roles in inflammatory diseases, explores its prospects as a therapeutic target, and provides a theoretical foundation for future drug development targeting GPR39.