Selenium is naturally present in the human body, animals, and plants, and is one of the important elements in their growth and maintenance. Recently, the nanoform of selenium has attracted attention due to its low toxicity and a high degree of adsorption compared to its organic and inorganic forms. The current study aimed to examine the effect of Cress leaves (Lepidium sativum L.) extract in combination with selenium nanoparticles in alleviating polycystic ovary syndrome in letrozole-induced PCOS in adult female rats. Nonthermal or cold plasma was used in the synthesis of selenium nanoparticles. Subsequently, the produced nanoparticles were identified, the 30 rats were divided into 6 equal groups, the first group was healthy (negative control); handled with distilled water given orally. To induce PCOS, rats were given letrozole (1 mg/kg) B.W daily for 21 days, The second group was left without any treatment (PCOS group), while the rats in the other 4 groups were treated orally and daily for 30 days using the following treatments: metformin (metformin group), Cress extract only (CE group), Cress extract with SeNPs (CE+SeNPs group), and SeNPs only (SeNPs group), respectively. Biochemical tests (Follicle stimulating, luteinizing, testosterone, and estrogen hormones as well as glucose and insulin levels) and histopathological analyses were performed. The results of the current study show a significant decrease in glucose and insulin levels, and a highly significant increase in LH, FSH, and testosterone levels while a significant decrease in estrogen levels in the Cress extract, SeNPs and metformin-treated groups with respect to PCOS induced group. The present study demonstrated the effect of SeNPs and Cress extract in the treatment of PCOS. SeNPs and Cress leaves extract improved ovarian dysfunction and reduced the number of ovarian cysts.