Background: Despite recent advances in hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) is still one of the most challenging post-transplant complications with a considerable mortality rate. Various strategies, including chemotherapy, depletion of T lymphocytes, monoclonal antibodies, corticosteroids, and other immunosuppressive drugs are used to reduce GVHD incidence, which usually increases the risk of cancer relapse and various infections in patients. The recently conducted studies have introduced oncolytic virotherapy as a promising solution to prevent GVHD and enhance the graft-versus-tumor effects. Oncolytic viruses are non-pathogenic viruses capable of selective lysis of cancer cells. These viruses can differentiate between allogeneic T lymphocytes and hematopoietic stem cells, and suppress allogeneic T cells. This review study aimed to discuss the mechanisms of oncolytic virotherapy in reducing the incidence of GVHD.