Objective：The current study aims to explore the effect and mechanism of hydroxychloroquine(HCQ)on lipopolysaccharide(LPS)induced neutrophil extracelluar traps(NET)in dextran sulfate sodium salt(DSS)induced colitis mice. Methods：Mice were randomly divided into control group，DSS group(3% DSS drinking water+200 μL pure water by gavage)，and DSS+HCQ group(3% DSS drinking water+200 μL HCQ of 60 mg/kg by gavage). The disease activity index(DAI)score was evaluated every day. The mice were killed after seven days，colon length of mice in each group were counted. The pathological changes of colon tissue of mice in each group were observed by HE staining；the NET level was detected by fluorescence microscope and fluorescence microplate reader. The peripheral blood of volunteers was collected to extract neutrophils for experiments in vitro，and the level of NET with fluorescence microscope and fluorescence microplateanalyzer was detected. The level of reactive oxygen species(ROS)was detected by fluorescence microplate analyzer after incubation with DCFH -DA fluorescence probe. The protein expression levels of p-MEK，MEK，p-ERK and ERK were detected by Western blot. Results：HCQ alleviated intestinal inflammation in DSS model mice by reducing the formation of NET in vivo and in vitro. In vitro，HCQ decreased the release of ROS，and inhibited the activation of MEK/ ERK signaling pathway. The MEK agonist C16-PAF reversed the inhibition of HCQ on MEK/ERK signaling pathway，enhanced the release of ROS，and then increased the formation of NET. Conclusion：HCQ can reduce DSS induced colitis in mice through reducing the release of ROS by inhibiting the MEK/ERK signal pathway，thereby reducing the intestinal damage caused by NET.