Abstract Background Ischemia–reperfusion injury (IRI)-induced acute kidney injury (AKI) can repair itself completely. However, most moderate and severe patients undergoing IRI-AKI progress to chronic kidney disease due to incomplete repair. The present study is aimed to investigate the role of bone marrow mesenchymal stem cell-derived exosomes (MSC-Exo) with indoleamine 2,3-dioxygenase (IDO) overexpression on incomplete repair in mice after IRI. Methods IRI mice was established by clamping the unilateral renal pedicles and challenged with MSC-Exo. Blood biochemical indexes and inflammation factors contents were measured by ELISA assay. Histopathological examinations were monitored by HE, Masson, Immunohistochemical and TUNEL staining. Immunofluorescence, flow cytometry and immunoblotting were used to detect the polarization of macrophages, respectively. Results As compared to sham operation mice, IRI mice showed high contents of serum BUN and Scr, and more severe damaged kidney tissues on days 1 and 3, which all gradually declined over time, showing the lowest level on day 7 after injury. Once treated with MSCs-Exo that could directly transfer to kidney tubular cells, the restoration of kidney functions significantly accelerated by contrast to IRI mice, and the promotive effects were more obvious in IDO-overexpressed MSCs-Exo (MSCs-Exo-IDO)-treated IRI mice. Furthermore, MSCs-Exo-IDO administration also accelerated renal tubular cells proliferation, restrained tubular cells apoptosis, fibrosis and inflammation factor secretions during self-repair process compared to IRI mice, whose effects were higher than MSCs-Exo-NC-challenged IRI mice and IDO overexpressing plasmid-injected IRI mice. Mechanistically, MSCs-Exo-NC and MSCs-Exo-IDO exposure promoted the polarization from M1 macrophage to M2 macrophage, leading to more anti-inflammatory factors production, and subsequently altered the inflammatory microenvironment of renal tubular cells, which facilitated the self-repair process in mice after IRI. Conclusion MSCs-derived exosome accelerated renal self-repair in IRI mice by activating M2 macrophages polarization, which effects were amplified by IDO overexpression in MSCs. Potentially, genetically modified MSCs-Exo is an effective approach to improve renal self-repair in IRI-AKI mice.