Mesenchymal stromal cells (MSCs) are known for their immunomodulatory properties, and their role in antiviral response is poorly understood. The susceptibility of the MSCs to viral infection or viral tropism toward MSCs can be emanated from few available literature evidences. What makes MSCs special is the ability to sustain infection and reciprocate through immune intermediates like antimicrobial peptides, cytokines, and secretomes. However, care has to be taken to understand that MSCs can transmit viral infections and are known for their vulnerability to many microorganisms in general. In the recent past, after deadly infections like Ebola, Zika, and HIV, COVID-19 had posed a great threat, where stem cell transplantation was a suggestive therapeutic model in some cases due to the cytokine storm and other additional biochemical, molecular, and transcriptional factors associated with the pathology. This is true in many other common viral infections at large. In this chapter, the role of MSCs in combating viral infections as well as their susceptibility pattern are discussed. Further, the role of MSCs in immunomodulation and their antiviral factors cannot be delineated in understanding the immunological mechanisms preventing tissue damages associated with viral infection.