<p>Chronic autoimmune inflammatory rheumatic and musculoskeletal diseases (iRMD such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc)) are characterized by the dysregulation of the immune system, leading to chronic inflammation and tissue damage. Traditional therapeutic approaches have focused on immunosuppressive drugs and biologics targeting specific cytokines or immune cells. However, these therapies often have limited efficacy and significant side effects. Moreover, they are not globally accessible due to high drug costs, especially in poor as well as low- to middle-income countries. In recent years, it is increasingly becoming apparent that exosomes, which are small extracellular vesicles involved in intercellular communication, could be promising novel therapeutic agents. Exosomes derived from various cell types and plants can exert immunomodulatory effects that can downregulate immune activation in autoimmune diseases. They can potentially overcome some of the limitations and challenges in cell immunotherapy. This paper reviews the potential of exosome-based therapies in iRMD, highlighting their mechanisms of action, therapeutic applications, preclinical and clinical studies, challenges, and future directions.</p>