The current study investigated the role of sRAGE in the production of IFN‑γ in macrophages with I/R treatment. The number of macrophages in myocardial tissues treated with I/R with or without sRAGE was determined via immunohistochemical staining. Proliferative activity of macrophages was analyzed by a 5‑BrdU incorporation assay. Differentiation of macrophages was detected via immunofluorescence staining of iNOS (M1 macrophage marker). IFN‑γ production, due to sRAGE stimulation, in Raw 264.7 macrophages and the NF‑κB signaling pathway were measured using western blotting. A ChIP assay was used to examine the interactions between NF‑κB and the promoter of IFN‑γ. The results showed that the number of macrophages in I/R‑treated myocardial tissues was increased following sRAGE infusion. Proliferation of macrophages was increased significantly in the presence of sRAGE; after I/R treatment, the cells preferred to differentiate into M1 macrophages. IFN‑γ expression in Raw 264.7 macrophages was suppressed by an NF‑κB inhibitor (Bay117082) but enhanced by sRAGE, with or without I/R treatment. Furthermore, sRAGE increased the phosphorylation of IκB, IKK and NF‑κB, as well as the translocation of NF‑κB into the nucleus of Raw 264.7 macrophages, with or without I/R treatment. ChIP results showed that sRAGE promoted NF‑κB binding to the promoter of IFN‑γ in Raw 264.7 macrophages. Therefore, the findings of the present study indicated that sRAGE protected the heart from I/R injuries, which might be mediated by promoting infiltration and the differentiation of macrophages into M1, which would then synthesize and secrete IFN‑γ through activating the NF‑κB signaling pathway.