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9‐aminacrine (9‐AA), an external antibacterial agent, possesses important bioactivities for the treatment of cancer, viruses, and prion diseases. Recent research has revealed that 9‐AA has anti‐inflammatory effects through the up‐regulation of nuclear receptor subfamily 4 group A member 1 (NR4A1), but it is highly cytotoxic. To mitigate its toxicity, three series of novel 9‐AA derivatives were synthesized. The toxicity of all compounds was assessed, and some of the less toxic compounds were tested for in vitro anti‐inflammatory activities, leading to the establishment of structure‐activity relationships. In particular, 9‐amino‐8‐bromo‐3,4‐dihydroacridin‐1(2H)‐one exhibited relatively low toxicity and retained anti‐inflammatory activity, with a higher selectivity index compared to 9‐AA (3.44 versus 0.68). Expression experiments of inflammatory mediators revealed that this compound not only inhibited the gene expression of pro‐inflammatory factors, but also promoted the gene expression of anti‐inflammatory factors. Preliminary mechanistic studies suggested that it exerted anti‐inflammatory effects through the NR4A1/Interleukin‐10 (IL‐10)/suppressors of cytokine signalling 3 (SOCS3) signaling pathway. Furthermore, molecular docking studies indicating that it may exhibit anti‐inflammatory activity by inhibiting the protein targets phosphodiesterase‐4 (PDE‐4) and p38 mitogen‐activated protein kinases (MAPK). Based on our data, 9‐amino‐8‐bromo‐3,4‐dihydroacridin‐1(2H)‐one with its low toxicity and anti‐inflammatory properties, holds promise for further development as an anti‐inflammatory agent. [ABSTRACT FROM AUTHOR]