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Raffia palm wine is a natural drink from the stem of Raffia palm (Raphia hookeri) tree with nutritional and medicinal properties. The effect of fermentation was investigated on its antidiabetic and antioxidative effects in yeast cells and pancreatic tissues, respectively. Both unfermented and fermented palm wine significantly increased glucose uptake, reduced glutathione level (GSH), superoxide dismutase, and catalase activities. They also inhibited glucose diffusion, myeloperoxidase, and ATPase activities as well as decreased malondialdehyde and nitric oxide levels. They also led to the inactivation of oxidative metabolic pathways in oxidative pancreas with the generation of adenosine, sugar and inositol metabolites, selenium (enzyme co‐factor) and vitamin metabolites owing to concomitant activation of vitamins, lipid, steroids, inositol, and sulfate/sulfite metabolic pathways. The results suggest the antidiabetic and antioxidative potentials of unfermented and fermented palm wine and may be attributed to the LC‐MS‐identified compounds which were mainly polyphenols and its glycosides, vitamins, and amino acids. Practical applications: Raffia palm wine is among the natural beverages employed for social, nutritional, and medicinal purposes. However, there are limited studies on its medicinal properties. This study reports for the first time, the ability of Raffia palm wine to stimulate glucose uptake, inhibit glucose diffusion, and ameliorate pancreatic oxidative injury, as well as the possible associated metabolic pathways that may be involved. These findings will further contribute in understanding the antidiabetic effect of Raffia palm wine, and the possible metabolic pathways involved. [ABSTRACT FROM AUTHOR]