Our understating of the mechanisms underlying the immunomodulatory properties of mesenchymal stem cells (MSCs) has greatly been advanced during previous decades. Considering their unique regulatory effects, numerous applications have been established for treating autoimmune diseases. However, cellular senescence and inefficient functions were found in MSCs isolated from autoimmune patients when they were particularly utilized in autologous settings. To date, several attempts were conducted to provide an in-depth understanding of mechanisms involved in MSC senescence and its negative impacts on autoimmune disease onset/ progression. Accordingly, indirect evidence of the role of immunosenescent MSCs has been reported during the immunopathogenesis of systemic sclerosis, osteoarthritis, systemic lupus erythematosus, diabetes, psoriasis, and immune thrombocytopenia. This connection is mediated primarily through reduced self-renewability of MSCs as well as their abnormal immunoregulatory functions in the polarization of immune cells. Such knowledge is critical for developing any therapeutic intervenes that is aimed to re-induce immune balance of autoimmune patients. To further explore the basic and clinical characteristics of MSC senescence in autoimmune disorders, this review comprehends the available information regarding molecular mechanisms and cellular interactions that finally perturb immuno-homeostasis of MSCs.