Beyond the conventional use of immunosuppressants in organ transplantation, it has multiple applications, including controlling autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. The recent pandemic of Covid -19 also sought its effectiveness in managing the later stage cytokine storm, which can otherwise lead to mortality. Regardless of recent advancements in the field, the considerably high cost of these agents is a limiting factor in organ transplantation that adds to the financial strain on patients with socioeconomic disparities. An in-depth analysis of the bioprocess engineering aspect of immunosuppressant drugs is essential to reveal the crucial points that can enhance the production of these secondary metabolites and show a way ahead for more economical production. This review aims to summarize past and current advances in bioprocessing strategies used in the field, emphasizing the production of cyclosporins, tacrolimus, mycophenolic acid, and sirolimus. An insight of producer microorganism, production parameters and their modulations as cutting-edge technology for enhanced production of these high-value and low-volume products has been provided in this study.