〔Abstract〕 Objective To investigate the effects of salidroside (SAL) on the impaired bioactivity of endothelial progenitor cells (EPCs) in atherosclerotic (As) mice and the potential mechanisms regarding AMP-activated protein kinase (AMPK). Methods Atherosclerosis was induced in 8-week-old male ApoE -/- mice with high-fat diet. Intragastric administration of SAL was given to one mice group to investigate the effects of SAL on aortic plaque burden, plasma NO level, the migration and angiogenic capabilities of bone marrow-derived EPCs (BM-EPCs). The proliferation, migration and vasculogenic properties of EPCs isolated from As mice were investigated in vitro. AMPK-sh-RNA or the AMPK inhibitor Compound C was used to investigate the role of AMPK/Akt/eNOS pathway in the regulatory effects of SAL. Results Compared with As group, NO level was significantly elevated in SAL group. The sizes of atherosclerotic plaques at the aortic root were reduced with smaller lipid cores in SAL group compared with As group. Moreover, the migration and angiogenesis capacity of EPCs markedly decreased in As mice, while SAL treatment reversed these impairments. Incubation with SAL at concentrations of 20, 40, and 80 μmol/L for 48 hours significantly promoted the proliferation, migration, and angiogenesis of EPCs. AMPK-sh-RNA transfection abrogated the SAL-mediated improvement in EPC biological activities. Western blot analysis further demonstrated that treatment with Compound C blocked the activation of AMPK/Akt/eNOS signaling pathway induced by SAL. Conclusion SAL upregulates the biological functions of EPCs through activating the AMPK/Akt/eNOS signaling pathway, thereby ameliorating EPC dysfunction during the pathological progression of atherosclerosis.