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Curcumin has a wide range of biological activities. This study investigated the anti-inflammatory activity of a triazole curcumin derivative (TAC)—especially its effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and possible targets. In the xylene-induced ear edema experiment, the inhibition rate of TAC against mice ear edema was 23.8%–78.2% over a dose range of 2.5–40 mg/kg 4 h after administration. At a dose of 10 mg/kg, the anti-inflammatory activity of TAC reached a peak at 4 h with an inhibition rate of 73.1%. This was significantly better than the positive control drug sodium diclofenac (DCF). TAC can also effectively reduce the degree of pulmonary edema injury in mice. H&E and Masson staining showed that the inflammatory and pathological indicators of LPS-induced lung injury were significantly improved by TAC. MTT tests illustrated that TAC showed weak cytotoxicity against RAW264.7 cells, and inhibited TNF-α and IL-6 release induced by LPS. Western blotting indicated that TAC decreased the expression of NF-κB and AP-1 in LPS pre-treated RAW264.7 cells, but failed to influence the expression of NF-κB in IL-1β pre-treated HET293T-Myd88−/− cells. Docking studies show that TAC could bind to the hydrophobic pocket of the CD2-TLR4 complex and expressed a high binding affinity. In conclusion, TAC exerts its anti-inflammatory effects by targeting the MD2-TLR4 signaling pathway, thus suggesting that it may be a promising candidate for the treatment of acute lung injury.