Stem cell transplantation is a promising clinical strategy for curing ischemic cardiomyopathy. However, its efficacy is impaired by low cell survival following transplantation, partly caused by insufficient resistance of the transplanted stem cells to severe oxidative stress at the injury site. In the current study, it was demonstrated that the small‑molecule macrophage migration inhibitory factor (MIF) enhanced the defense of bone marrow‑derived mesenchymal stem cells (MSCs) against hypoxia/serum deprivation (SD)‑induced apoptosis in vitro. MIF significantly suppressed apoptosis and caspase family activities through inhibition of long intergenic noncoding (linc) RNA‑p21 to maintain activation of the Wnt/β‑catenin signaling pathway. The regulatory loop between MIF and the lincRNA‑p21‑Wnt/β‑catenin signaling pathway was identified to be associated with the inhibition of oxidative stress. The involvement of the lincRNA‑p21‑Wnt/β‑catenin signaling pathway in the effects of MIF in MSCs by overexpression of lincRNA‑p21and silencing β‑catenin using small interfering RNA was also demonstrated, both of which abolished the anti‑apoptotic and anti‑oxidative effects of MIF in MSCs under hypoxia/SD conditions. In conclusion, MIF protected MSCs from hypoxia/SD‑induced apoptosis by interacting with lincRNA‑p21, leading to activation of the downstream Wnt/β‑catenin signaling pathway and decreased oxidative stress. Thus, treatment with MIF may have important therapeutic implications in improving MSC survival and therapeutic efficiency.