Histone deacetylase inhibitors (HDACi) have gained attention for their potential therapeutic effects in various immune-related diseases and solid organ transplantation. This review focuses on the role of HDACs’ expression in immune responses, especially of T and B cells, in organ transplant rejection. We examined the expression levels of HDACs in T and B cells across different immune states, providing insight into their regulatory functions during immune activation and tolerance. Through an analysis of in vitro, in vivo, and preclinical studies, we explored the effects of HDACi on immune modulation, highlighting their impact on T- and B-cell function in diseases other than cancer. Finally, we discussed the outcomes of HDACi treatment in various organ transplantation models, assessing their potential to mitigate rejection, promote tolerance, and improve graft survival. The review synthesizes current evidence, identifies knowledge gaps, and offers a comprehensive outlook on HDACi for clinical applications in organ transplantation.