Objective To investigate intestinal mucosal injury induced by Clopidogrel in mice and potential molecular mechanism. Method Twenty SPF grade BALB/C male mice were randomly divided into control group and Clopidogrel group. Mice in Clopidogrel group were treated with Clopidogrel while mice in control group was fed with normal saline. Mice were sacrificed after 2 weeks. Macroscopic and histological changes of the small intestinal mucosa in the two groups were recorded. Expression of Occludin in small intestinal mucosa was determined by immunohistochemistry. Results The macroscopic damage and the histopathologic damage of small intestinal mucosa in Clopidogrel group were significantly higher than those in control group (P < 0.05). The expression of Occludin protein in small intestinal mucosa was decreased significantly with treatment of Clopidogrel compared with control group (P < 0.05). Conclusions Clopidogrel induces small intestinal mucosa damage through reduction of Occludin expression and inhibition of the repair of small intestinal mucosal injury.