Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age, characterized by hormonal imbalances, insulin resistance, and metabolic disturbances. The KiSS-1 gene, which encodes the kisspeptin neuropeptide, is crucial for regulating reproductive hormones through the hypothalamic-pituitary-gonadal axis. Genetic polymorphisms in KiSS1 diminish kisspeptin activity and exacerbate PCOS symptoms. This study investigates the potential of bioactive compounds from Lepidium sativum (garden cress) to modulate KiSS-1 gene function and address PCOS-related dysfunctions. A set of eight bioactive compounds from Lepidium sativum was screened using molecular docking with Virtual Screening software for Computational Drug Discovery to assess their interactions with wild-type and polymorphic forms of the KiSS-1 gene. The chemical structures of the compounds were designed using ChemSketch and are visualized for molecular interactions using BIOVIA Discovery Studio. Sequence data for the wild-type and polymorphic variants of the KiSS-1 gene were obtained from the Protein Data Bank and the National Center for Biotechnology Information. Pharmacokinetic properties and drug-likeness of the selected compounds were evaluated using SwissADME, with particular reference to Lipinski’s Rule of Five criteria. Alpha-linolenic acid, oleic acid methyl ester, stigmasterol, and α-D-glucopyranoside exhibited strong binding affinities and established stable interactions with the wild-type and polymorphic forms of the KiSS-1 gene. Among them, alpha-linolenic acid and stigmasterol showed the most favorable binding profiles, characterized by stable hydrogen bonding and high binding energy values, indicating strong potential as modulators of KiSS-1 activity. Notably, the binding affinity of alpha-linolenic acid was reduced in the polymorphic variant compared to the wild-type, supporting the hypothesis of diminished gene function associated with PCOS-related polymorphisms. SwissADME analysis confirmed that these top candidates possess favorable pharmacokinetic properties and comply with Lipinski’s Rule of Five, suggesting good oral bioavailability and drug-likeness. This computational study suggests that bioactive compounds from Lepidium sativum have the potential to interact effectively with both wild-type and polymorphic forms of the KiSS-1 gene. Their strong binding affinities indicate a possible role in restoring gene function, which may contribute to alleviate symptoms of POCS. The study considers epigenetic mechanisms such as DNA methylation and histone modification through which these compounds may enhance KiSS-1 gene expression. This dual mechanism positions Lepidium sativum as a promising plant-based therapeutic candidate for PCOS.