GPR84 is a proinflammatory G protein-coupled receptor associated with several inflammatory and fibrotic diseases. GPR84 antagonists have been evaluated in clinical trials to treat ulcerative colitis, idiopathic pulmonary fibrosis, and nonalcoholic steatohepatitis. However, the variety of potent and selective GPR84 antagonists is still limited. Through high-throughput screening, a novel phosphodiester compound hit 1 was identified as a GPR84 antagonist. The subsequent structural optimization led to the identification of compound 33 with improved potency in the calcium mobilization assay and the ability to inhibit the chemotaxis of neutrophils and macrophages upon GPR84 activation. In a DSS-induced mouse model of ulcerative colitis, compound 33 significantly alleviated colitis symptoms and reduced the disease activity index score at oral doses of 25 mg/kg qd, with an efficacy similar to that of positive control 5-aminosalicylic acid (200 mg/kg, qd, po), suggesting that compound 33 is a promising candidate for further drug development.