Mesenchymal stem cells (MSCs), as one of the leading cell-based therapy, have provided a strong link between clinical investigation and basic research. MSCs have been successfully employed in treating graft versus host disease (GvHD), autoimmune disease, spinal cord injury, and several other diseases, particularly with high immunity activity. Recently, MSCs have attracted attention to treating untreatable viral infections such as severe coronavirus disease 2019 (COVID-19). Given that the Toll-like receptors (TLRs) are directly able to detect internal and external hazard signals, and their stimulation has an intense effect on the ability to grow, differentiate, migrate, and survive MSCs, it seems stimulation of these receptors can have a direct impact on the interaction of MSCs and immune cells, altering the ability to modify immune system responses. Hence, this brief review focused on the critical roles of TLRs on the polarization of MSCs for developing MSC-based therapy in viral infections. Consequently, according to the literature review, a polarization process mediated by TLRs, concerning both anti-inflammatory and pro-inflammatory phenotype, may be considered for MSC-therapy against viral infections.