Background: Social Isolation (SI) is an influential stressor in animals and humans, which has a negative impact on mental and physical health. It is associated with increased oxidative stress and decreased antioxidant capacity. Melatonin (MT) is well known by its antioxidant properties that help in prevention of tissue damage. Aim of Study: The present study aimed to investigate the harmful effect of SI on rat ovary and the possible protective role of MT. Material and Methods: Twenty adult female albino rats were divided into four groups; five rats in each (control, MT, SI and SI + MT). Histological examination was done using hematoxylin and eosin, semithin sections were stained with toluidine blue and ultrathin sections were performed. Measurements of Malondialdehyde (MDA) and Superoxide Dismutase (SOD) activity in ovarian tissue were carried out. Quantitative analysis of SIRT1 gene expression was done by real-time Polymerase Chain Reaction (PCR). Morphometric measurements were also performed. Results: Light microscopic examination of ovarian follicles from SI group showed shrunken granulosa cells with pyknotic nuclei and irregular oocytes with rarified cytoplasm. Cytoplasmic vacuolation was observed in granulosa cells, theca cells and granulosa lutein cells. Ultrastructural examination of granulocsa cells showed swollen mitochondria and abundant lipid droplets. The oocytes exhibited disrupted microvilli. There was significant decrease in the mean follicular diameter, granulosa and theca layer thickness in SI group compared to control group. These morphological changes were associated with significant increase in MDA and decrease in SOD activity, in addition to increased SIRT1 gene expression. Concomitant administration of MT improved the previously mentioned alterations. Conclusion: Social isolation induced histological, ultrastructural and morphometric changes in the ovary of rats. These changes were associated with oxidative stress, decreased antioxidant capacity and increased SIRT1 gene expression.