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Introduction Aging is a normal physiological process that affects all organs in the body including the cerebellum. Metformin is an anti-diabetic drug that is used in some age-related diseases. Regenerative medicine using adipose tissue derived mesenchymal stem cells (ADMSCs) is an emerging promising strategy. Aim to compare between the role of ADMSCs and metformin on the age-related structural changes of the cerebellum in female albino rats. Materials and methods Fifty-five female rats of different ages (4, 12 and 24 months) were included in this study. They were divided into three groups according to their ages: Group I (Adult rats), Group II (Old rats) and Group III (Senile rats). Group II and Group III were subdivided into three subgroups, Subgroup a: rats were left without treatment, Subgroup b: rats were given a single dose of 1X106 ADMSCs via tail vein. Subgroup c: Rats received300 mg/kg metformin/day orally. Rats were sacrificed after four weeks. The cerebellum was collected and processed for H&E, Toluidine blue and immuno-histochemical reaction using glial fibrillary acidic protein (GFAP). Results Histological examination of the cerebellum of the subgroups IIa and IIIa revealed age-related structural changes in comparison to group I. Purkinje cells appeared distorted with irregular outline. Some Purkinje cells were seen shrunken while others appeared ballooned. Focal loss of Purkinje cells was also noticed. Granular layer contained small widely separated granule cells. GFAP reaction revealed an apparent decrease in number of astrocytes and their processes. The structural changes were more obvious in subgroup IIIa. In ADMSCs treated subgroups (IIbandIIIb); more noticeable improvement of these changes was noticed compared to the corresponding metformin treated subgroups (IIc and IIIc). Conclusion ADMSCs was more effective than metformin in preventing some age-related structural changes of the cerebellum.