Purpose <p>Diabetes mellitus is a significant public health issue. Despite the emergence of promising anti-hyperglycemic drugs, treatment outcomes for diabetic patients continue to be inadequate. Gypenosides are the major bioactive compounds isolated from <i>Gynostemma pentaphyllum</i> (Thunb.) Makino. <i>Gynostemma pentaphyllum</i> has longstanding history of usage in traditional oriental medicine, particularly for the treatment of diabetes mellitus. Gypenosides were found to exhibit antidiabetic effects. This review outlined the advancements in the preclinical studies of gypenosides’ pharmacological properties on diabetes mellitus and their potential mechanism of action, while also noting the lack of clinical evidence for gypenosides’ efficacy.</p> Methods <p>Literatures search was done using scientific databases PubMed, Web of Science, Scopus and Google Scholar up to November 2024 utilizing keywords such as "<i>Gynostemma pentaphyllum</i>", "gypenoside*", and "diabet*".</p> Results <p>Research has shown that gypenosides possess therapeutic properties in mitigating diabetes mellitus by regulating blood glucose levels and insulin production. Gypenosides can modulate various key pathways associated with diabetes pathogenesis, including PI3K/Akt, PPARγ, NF-κB, AMPK and PDX1, hence contributing to their antidiabetic properties. Nevertheless, there is a paucity of research on gypenosides in clinical settings, with existing studies being mainly conducted on animal models and in vitro. Future studies with the focus on the isolation and purification of specific gypenosides, as well as the exploration on the probable pharmacological effect and molecular mechanisms behind the biological actions are necessary.</p> Conclusion <p>The findings presented may establish a foundation for subsequent clinical trials for the development of specific gypenosides as antidiabetic therapies for the betterment of human health.</p> Graphical Abstract <p></p>