In recent years, there has been growing interest in using Nanosystems in different biomedical applications. Among all metal nanoparticles, selenium nanoparticles have attracted the attention of many researchers due to its low toxicity and nutritional supplementation value. The purpose of the current study was designed to examine the possible effect of selenium nanoparticles in combination with fenugreek leaves extract (an edible herb with good medicinal properties) in the treatment of oxidative stress status-related to polycystic ovary syndrome in letrozole-induced PCOS (an imbalance of reproductive hormones that causes infertility) in adult female rats. Cold plasma was used in the preparation of selenium nanoparticles subsequently the produced nanoparticles were characterized. Thirty rats were divided into six equal groups, including a healthy rat handled with distilled water given orally. To induce the PCOS, rats were given letrozole (1 mg/kg) B.W daily for 21 days, (the letrozole was dissolved in 1% carboxymethylcellulose. The second group was left without any treatment (PCOS group), and the rats in the other 4 groups were treated orally and daily for 30 days using the following treatments: metformin, fenugreek extract only, SeNPs only, and fenugreek extract with SeNPs, where used SeNPs at 10 min of exposure to plasma. Biochemical tests (amylase, superoxide dismutase, and malondialchehyche) levels as well as histopathological examination were performed. The outcomes of the present study show the effective effect selenium nanoparticles in combination with fenugreek leaves extract for the PCOS treatment which can be suggested as a new drug in the PCOS management.