Natural polybrominated diphenyl ethers are generally isolated from sponges and possess a broad range of biological activities. Through screening of our marine natural product library, we discovered that polybrominated diphenyl ethers 5 and 6 exhibit considerable anti‐inflammatory activity. In order to expand our repertoire of derivatives for further biological activity studies, we designed and synthesized a series of 5‐related polybrominated diphenyl ethers. Importantly, compound 5a showed comparable anti‐inflammatory activity while much lower cytotoxicity on lipopolysaccharide (LPS)‐induced RAW264.7 cells. Additionally, western blotting analysis showed that 5a reduced the expression of phosphorylated extracellular signal‐regulated kinase (p‐ERK). Besides, molecular docking experiments were conducted to predict and elucidate the potential mechanisms underlying the varying anti‐inflammatory activities exhibited by compounds 5a, 5, and 6.