Background: Isoxicam is a member of nonsteroidal anti-inflammatory drugs (NSAIDs) that reduces pain, decreases fever, prevents blood clots, and in higher doses decreases inflammation. Aim of the work: The aim of this work is to investigate the harmful effect of Isoxicam on the ovary and the possible antagonistic effect of Melatonin. Material and methods: Isoxicam were obtained from Beecham pharmaceutical, Cairo, Egypt. Fifty-four albino rats were used throughout the study. The rats were assigned into three groups eighteen female albino rats in each group. Group I:  Received saline intraperitoneally. Group II: The rats were injected with 0.7gm/kg isoxicam intraperitoneally for 20 days. Group III: The rats were injected with 0.7mg/kg isoxicam + 10mg/kg melatonin intraperitoneally for 20 days. Ovaries were removed and prepared for histological and ultrastructural analyses. Results: Isoxicam induced marked histopathological ovarian changes that were remarkably ameliorated by the prophylactic use of Melatonin. Conclusion: This work revealed a prophylactic role of melatonin in isoxicam induced ovarian damage. Thus, melatonin administration is recommended for female patients when isoxicam is used for long time to avoid ovarian damage.