Myocardial infraction (MI) is a severe disease with great mortality. Mesenchymal stem cells‐derived exosomes display protection against MI. MicroRNA‐129‐5p was reported to exert anti‐inflammation activity by targeting high mobility group box 1 (HMGB1). In the present study, the effects of MSCs derived exosomes overexpressing miR‐129‐5p on MI were evaluated. Bone marrow mesenchymal stem cells (BMSCs) were transfected with miR‐129‐5p for exosomes isolation. Myocardial infraction mice model was established and administrated exosomes overexpressing miR‐129‐5p. The cardiac function, expression of HMGB1, inflammatory cytokines, apoptosis and fibrosis in heart tissues were measured. miR‐129‐5p inhibited HMGB1 expression in BMSCs. Myocardial infraction mice treated with exosomes overexpressing miR‐129‐5p had enhanced cardiac function and decreased expression of HMGB1 and production of inflammatory cytokines. Exosomes overexpressing miR‐129‐5p further prevented apoptosis and fibrosis. Exosome‐mediated transfer of miR‐129‐5p suppressed inflammation in MI mice by targeting HMGB1.