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Background: Graft-versus-host disease (GVHD) continues to emerge as the topmost causative factor of the morbidity and mortality rate post hematopoietic stem cell transplantation. The graft cells attack the recipient host tissues resulting in acute or chronic GVHD that affect organs, including the lung, liver, skin, and gastrointestinal tract. Certain factors are considered to play a crucial role in the progression of the disease, such as antibodies produced by B cells, reduction in regulatory T cells, and immune tolerance disruption to self-antigen. Main body: This review highlighted the pathophysiology of GVHD, clinical manifestation, stages of GVHD in different organs, and the significant role played by Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) in cytokine signalling, development, and function of several immune cells. Furthermore, we discussed the clinical efficacy of drugs, which comprises JAK inhibitors, monoclonal antibodies, and proteasome inhibitors that are widely used to treat GVHD. Conclusion: Considering the progress recorded in identifying the therapeutic regimens for GVHD, novel and effective therapeutic approaches are much needed to alleviate the complication that arises post hematopoietic stem cell transplantation and reduce the morbidity and mortality rate of the disease.