Objective To examine the role and mechanism of clopidogrel in the development of salt-sensitive hypertension. Methods 8-week-old Dahl salt-sensitive (Dahl SS) rats and control salt-resistant (SS13^BN) rats were divided randomly into six groups and fed for 8 weeks with normal salt (0.4% NaCl, NS), high salt (8% NaCl, HS), or high salt combined with clopidogrel gavage (8% NaCl+10 mg/(kg·d)) clopidogrel, HS+CLO). Arterial systolic blood pressure was measured continuously over 8 weeks by the tail-cuff method, and systolic blood pressure was measured by carotid cannulation after 8 weeks (56 days). Renal histopathology was observed by hematoxylin and eosin staining, and renal inflammatory cell infiltration was detected by immunohistochemistry. Peripheral blood platelet activation and platelet-leukocyte aggregation were analyzed by flow cytometry, and the renal inflammationrelated proteins tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and key proteins in the p38MAPK/nuclear factor (NF)-κB signaling pathway were detected by Western blot. Results Compared with the NS group, Dahl SS HS rats had significantly increased blood pressure(P<0.05), aggravated renal tissue damage, increased inflammatory cell infiltration, increased expression of inflammatory cytokines(P<0.05), elevated peripheral blood platelet activation(P<0.05)and platelet-leukocyte aggregation(P<0.05), and increased expression of p38MAPK/NF-κB signaling pathway proteins(P<0.05). Clopidogrel effectively alleviated these phenotypes induced by high salt in Dahl SS rats. Conclusions Clopidogrel alleviated high-salt-induced salt-sensitive hypertension and decreased renal inflammatory responses and dysfunction in Dahl SS rats by inhibiting platelet activation and the p38MAPK/NF-κB signaling pathway.